Heteroaryl substituted heterocyclyl sulfones

ABSTRACT

The invention relates to aryl substituted heterocyclyl sulfones as voltage gated calcium channel blockers, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.

This application claims priority of European Patent Application No.14001346.7, filed Apr. 14, 2014, the entire contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to heteroaryl-substituted heterocycl sulfones asvoltage gated Ca-channel (CaV) blockers, to pharmaceutical compositionscontaining these compounds and also to these compounds for use in thetreatment and/or prophylaxis of pain and further diseases and/ordisorders.

BACKGROUND OF THE INVENTION

Ion channels are proteins that form pores in membranes of biologicalcells and control the flow of ions down their electrochemical gradient.They are involved in the regulation of a wide range of cellularfunctions in both excitable and nonexcitable cells and provideattractive therapeutic targets for the treatment of various diseases.

In the somatosensory context, CaV2.2 channels, specific cellular plasmamembrane calcium channels that belong to a diverse superfamily ofvoltage-gated calcium channels (VGCCs), were demonstrated to play animportant role in spinal nociceptive processing.

The critical role of CaV2.2 in pain processing was underlined by theclinical efficacy of the intrathecally delivered, selective CaV2.2channel antagonist Ziconotide (SNX-111; Prialt™), a synthetic peptidederived from a ω-(omega)-conotoxin peptide (Miljanich, 2004, Curr. Med.Chem., 11(23), p. 3029-40; Staats et al., 2004, JAMA, 291(1), p. 63-70).Inthrathecal administration of Ziconotide is required in order to reachthe ion channel in presynaptic terminals of sensory neurons in thespinal cord. Common side effects of Ziconotide include memoryimpairment, dizziness, nystagmus, speech disorder, nervousness,somnolence and abnormal gait (Rauck et al., 2009, Pain Pract., 9, p.327-37), which have been attributed to the inhibition of CaV2.2 channelsin the brain by Ziconotide.

Therefore, a demand remains for the development of orally availableCaV2.2 calcium channel blockers that show the desired qualities andeffectively block CaV2.2 calcium channels in the nociceptive signalingpathway.

SUMMARY OF THE INVENTION

The present invention describes small molecule CaV2.2 channel blockers.Sulfonamide based CaV2.2 channel modulatros are known from WO2007/125398.

It was therefore an object of the invention to provide novel compounds,preferably having advantages over the prior-art compounds. The compoundsshould be suitable in particular as pharmacological active ingredientsin pharmaceutical compositions, preferably in pharmaceuticalcompositions for the treatment and/or prophylaxis of disorders ordiseases which are at least partially mediated by CaV2.2 calciumchannels.

This object is achieved by the subject matter described herein.

The present invention therefore relates to a compound of general formula(I),

wherein

-   m represents 0, 1 or 2;-   n denotes 0 or 1;-   Y is selected from the group consisting of bond and —C(R³)₂—;    -   wherein each R³ is independently selected from the group        consisting of H and C₁₋₆-alkyl, or two R³ form together with the        C-atom connecting them a C₃₋₁₀-cycloalkyl or a 3 to 7 membered        heterocyclyl;-   L is —[C(R⁴)₂]_(x)—(X)_(y)—[C(R⁴)₂]_(z-),    -   wherein x is 0, 1 or 2, y is 0 or 1 and z is 0 or 1, with the        proviso that x≧y;    -   each R⁴ is independently selected from the group consisting of H        and C₁₋₆-alkyl,    -   or two R⁴ form together with the C-atom connecting them a        C₃₋₁₀-cycloalkyl or a 3 to 7 membered heterocyclyl or two R⁴        form together with two adjacent C-atoms connecting them a        C₃₋₁₀-cycloalkyl or a 3 to 7 membered heterocyclyl, X is        selected from the group consisting of O, S, S(O)₂, N(H) or        N(C₁₋₆-alkyl);-   R¹ is selected from the group consisting of H; F; Cl; CN;    C₁₋₆-alkyl; C₁₋₆-alkyl-O(R⁵) and C₁₋₆-alkyl-N(R⁵)₂;    -   wherein each R⁵ is independently selected from H or C₁₋₆-alkyl        or two R⁵ form together with the N-atom connecting them a 3 to 7        membered heterocyclyl;-   R² is selected from the group consisting of H; F; Cl; CN;    C₁₋₆-alkyl; C₁₋₆-alkyl-O(R⁶) and C₁₋₆-alkyl-N(R⁸)₂;    -   wherein each R⁶ is independently selected from H or C₁₋₆-alkyl        or two R⁶ form together with the N-atom connecting them a 3 to 7        membered heterocyclyl;-   Ar¹ represents aryl or heteroaryl, wherein said aryl or said    heteroaryl is substituted by zero or one or two or three    substituents R⁷,-   Ar² represents heteroaryl, substituted by zero or one or two or    three substituents R⁸,    -   wherein each R⁷ and each R⁸ is independently selected from the        group consisting of F; Cl; Br; I; NO₂; CN; C₁₋₆-alkyl; CF₃;        CF₂H; CFH₂; CF₂Cl; CFCl₂; C(═O)—H; C(═O)—C₁₋₆-alkyl; C(═O)—OH;        C(═O)—O—C₁₋₆-alkyl; C(═O)—N(H)(OH); C(═O)—NH₂;        C(═O)—N(H)(C₁₋₆-alkyl); C(═O)—N(C₁₋₆-alkyl)₂; C(═N—OH)—H;        C(═N—OH)—C₁₋₆-alkyl; C(═N—O—C₁₋₆-alkyl)-H;        C(═N—O—C₁₋₆-alkyl)-C₁₋₆-alkyl; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl;        OCFCl₂; O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; O—C(═O)—O—C₁₋₆-alkyl;        O—(C═O)—N(H)(C₁₋₆-alkyl); O—C(═O)—N(C₁₋₆-alkyl)₂;        O—S(═O)₂—C₁₋₆-alkyl; O—S(═O)₂—OH; O—S(═O)₂—O—C₁₋₆-alkyl;        O—S(═O)₂—NH₂; O—S(═O)₂—N(H)(C₁₋₆-alkyl);        O—S(═O)₂—N(C₁₋₆-alkyl)₂; NH₂; N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂;        N(H)—C(═O)—C₁₋₆-alkyl; N(H)—C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—NH₂;        N(H)—C(═O)—N(H)(C₁₋₆-alkyl); N(H)—C(═O)—N(C₁₋₆-alkyl)₂;        N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;        N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—NH₂;        N(C₁₋₆-alkyl)-C(═O)—N(H)(C₁₋₆-alkyl);        N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; N(H)—S(═O)₂OH;        N(H)—S(═O)₂—C₁₋₆-alkyl; N(H)—S(═O)₂—O—C₁₋₆-alkyl;        N(H)—S(═O)₂—NH₂; N(H)—S(═O)₂—N(H)(C₁₋₆-alkyl);        N(H)—S(═O)₂N(C₁₋₆-alkyl)₂; N(C₁₋₆-alkyl)-S(═O)₂—OH;        N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;        N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-S(═O)₂—NH₂;        N(C₁₋₆-alkyl)-S(═O)₂—N(H)(C₁₋₆-alkyl);        N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; SH; SCF₃; SCF₂H; SCFH₂;        SCF₂Cl; SCFCl₂; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl;        S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH; S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂;        S(═O)₂—N(H)(C₁₋₆-alkyl); S(═O)₂—N(C₁₋₆-alkyl)₂;        C₃₋₁₀-cycloalkyl; 3 to 7 membered heterocyclyl; aryl;        heteroaryl; O—C₃₋₁₀-cycloalkyl; O-(3 to 7 membered        heterocyclyl); O-aryl; O-heteroaryl; N(H)—C₃₋₁₀-cycloalkyl;        N(H)-(3 to 7 membered heterocyclyl); N(H)-aryl; N(H)-heteroaryl;        N(C₁₋₆-alkyl)-C₃₋₁₀-cycloalkyl; N(C₁₋₆-alkyl)-(3 to 7 membered        heterocyclyl); N(C₁₋₆-alkyl)-aryl; N(C₁₋₆-alkyl)-heteroaryl;        C(═O)—C₃₋₁₀-cycloalkyl; C(═O)-(3 to 7 membered heterocyclyl);        C(═O)-aryl; C(═O)-heteroaryl; S(═O)₂—C₃₋₁₀-cycloalkyl; S(═O)₂-(3        to 7 membered heterocyclyl); S(═O)₂-aryl; S(═O)₂-heteroaryl;        S(═O)(═NR¹³)—C₃₋₁₀-cycloalkyl; S(═O)(═NR¹³)-(3 to 7 membered        heterocyclyl); S(═O)(═NR¹³)-aryl and S(═O)(═NR¹³)-heteroaryl,        wherein R¹³ represents H or C₁₋₆-alkyl;        wherein in each case said C₁₋₆-alkyl may be branched or        unbranched; unsubstituted or mono- or polysubstituted; and        wherein in each case said C₃₋₁₀-cycloalkyl, 3 to 7 membered        heterocyclyl aryl and heteroaryl may be unsubstituted or mono-        or polysubstituted;        optionally in the form of an individual stereoisomer or a        mixture of stereoisomers, in the form of the free compound        and/or a physiologically acceptable salt and/or a        physiologically acceptable solvate thereof.

DETAILED DESCRIPTION

The term “single stereoisomer” preferably means in the sense of thepresent invention an individual enantiomer or diastereomer. The term“mixture of stereoisomers” means in the sense of this invention theracemate and mixtures of enantiomers and/or diastereomers in any mixingratio.

The compounds according to general formula (I) possess at least 2stereogenic carbon atoms: the carbon atom bearing R¹ and the carbon atombearing R².

The compounds according to formula (I) may be stereochemicallydifferentiated according to their relative structural orientation. Thecompounds wherein the residues R¹ and R² have the same relativeorientation, for instance both up (“bold wedge”) or both down (“brokenwedge”) are referred within the scope of the present invention as the“cis” diastereomer (scheme 1). The compounds wherein the residues R¹ andR² have a differented relative orientation, for instance R¹ up (“boldwedge”) and R² down (“broken wedge”) or vice versa are referred withinthe scope of the present invention as the “trans” diastereomer (scheme2).

Diastereoisomers differ with respect to their physical and chemicalproperties. Methods to determine the diatsereomeric ratio (dr) are wellknown to the person skilled in the art and include, but are not limitedto, NMR-methods.

A diastereomerically pure compound or a diastereomer according to thepresent invention refers to a stereoisomer, having a diastereomericratio of >90:10, particularly >92:8, preferably >95:5, morepreferably >98:2 and even more preferably >99:1.

For both diastereomers, two enantiomers are possible.

An enantiomerically pure compound or an enantionmer according to thepresent invention refers to a stereoisomer, having an enatiomeric excessof >90% ee, particularly >92% ee, preferably >95% ee, morepreferably >98% ee and even more preferably >98% ee. A racemic mixtureor a racemate refers to an equal mixture of two correspondingenantiomers.

Methods to determine the enatiomeric excess are well known to the personskilled in the art and include, but are not limited to, optical rotarydispersion, circular dichroism, NMR-methods using chiral auxiliaries(“shift reagents”) or separation via chiral HPLC (high performanceliquid chromatography, using a chiral stationary phase), chiral GLC(gas-liquid chromatography, using a chiral stationary phase) or chiralSFC (supercritical fluid chromatography using a chiral stationaryphase).

Determination of the absolute stereochemical structure is well known tothe person skilled in the art and includes, but are not limited to,x-ray diffractometry.

The stereogenic information of the compounds of the present invention isdescribed according to their relative chemical structure as detailedbelow:

-   1) A cis racemic compound (cis-rac) refers to a racemic mixture of    two enantiomers as depicted in scheme 1.

-   2) A trans racemic compound (trans-rac) refers to a racemic mixture    of two enantiomers as depicted in scheme 2.

-   3) A cis enantiomer 1 compound (cis-EN1) refers to one single    enantiomer as depicted in scheme 3.

-   4) A cis enantiomer 2 compound (cis-EN2) refers to the other single    enantiomer, which is not cis-EN1 as depicted in scheme 3.

-   5) A trans enantiomer 1 compound (trans-EN1) refers to one single    enantiomer as depicted in scheme 4.

-   6) A trans enantiomer 2 compound (trans-EN2) refers to the other    single enantiomer, which is not trans-EN1 as depicted in scheme 4.

The term “physiologically acceptable salt” preferably comprises in thesense of this invention a salt of at least one compound according to thepresent invention and at least one physiologically acceptable acid orbase.

The term “physiologically acceptable solvate” preferably comprises inthe sense of this invention an adduct of one compound according to thepresent invention and/or a physiologically acceptable salt of at leastone compound according to the present invention with distinct molecularequivalents of one solvent or more solvents.

The term “C₁₋₆-alkyl” comprise in the sense of this invention acyclicsat. aliphatic hydrocarbon residues, which can be respectively branchedor unbranched and can be unsubstituted or can be mono- orpolysubstituted, e.g. mono-, di- or trisubstituted, and which contain 1to 6 carbon atoms, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. PreferredC₁₋₆-alkyl groups are selected from the group consisting of methyl,ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl,n-pentyl, isopentyl, neopentyl, and n-hexyl.

In relation to the term “C₁₋₆-alkyl” the term “monosubstituted” or“polysubstituted” such as di- or tri-substituted refers in the sense ofthis invention, with respect to the corresponding groups, to the singlesubstitution or multiple substitution, e.g. disubstitution ortrisubstitution, of one or more hydrogen atoms each independently of oneanother by at least one substituent. The term “polysubstituted” such asdi- or tri-substituted with respect to polysubstituted groups such asdi- or tri-substituted groups includes the polysubstitution of thesegroups either on different or on the same atoms, for exampletrisubstituted on the same carbon atom, as in the case of CF₃ or CH₂CF₃or at various points, as in the case of CH(OH)CH₂CH₂CHCl₂. The multiplesubstitution can be carried out using the same or using differentsubstituents.

The term “C₃₋₁₀-cycloalkyl” mean for the purposes of this inventioncyclic aliphatic hydrocarbons containing 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms, respectively, wherein the hydrocarbons in each case can besat. or unsat. (but not aromatic), unsubstituted or mono- orpolysubstituted. The cycloalkyl group can be bound to the respectivesuperordinate general structure via any desired and possible ring memberof the cycloalkyl group. The cycloalkyl group can also be condensed withfurther sat., (partially) unsat., (hetero)cyclic, aromatic orheteroaromatic ring systems, i.e. with cycloalkyl, heterocyclyl, aryl orheteroaryl residues, which in each case can in turn be unsubstituted ormono- or polysubstituted. C₃₋₁₀-cycloalkyls can furthermore be singly ormultiply bridged such as, for example, in the case of adamantyl,bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl. Preferred C₃₋₁₀-cycloalkylgroups are selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, adamantly, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl,

Particularly preferred C₃₋₁₀-cycloalkyl groups are C₃₋₆-cycloalkylgroups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopentenyl and cyclohexenyl, in particular cyclopropyl.

The terms “3 to 7-membered heterocyclyl” mean for the purposes of thisinvention heterocycloaliphatic sat. or unsat. (but not aromatic)residues having 3 to 7, i.e. 3, 4, 5, 6 or 7 ring members, respectively,in which in each case at least one, if appropriate also two or threecarbon atoms are replaced by a heteroatom or a heteroatom group eachselected independently of one another from the group consisting of O, S,S(═O), S(═O)₂, N, NH and N(C₁₋₆-alkyl) such as N(CH₃), wherein the ringmembers can be unsubstituted or mono- or polysubstituted. The cycloalkylgroups can also be condensed with further sat. or (partially) unsat.cycloalkyl or heterocyclyl, aromatic or heteroaromatic ring systems,which in each case can in turn be unsubstituted or mono- orpolysubstituted. The heterocyclyl group can be bound to thesuperordinate general structure via any desired and possible ring memberof the heterocycloaliphatic residue if not indicated otherwise.

The term “aryl” means for the purpose of this invention aromatichydrocarbons having 6 to 14, i.e. 6, 7, 8, 9, 10, 11, 12, 13 or 14 ringmembers, preferably having 6 to 10, i.e. 6, 7, 8, 9 or 10 ring members,including phenyls and naphthyls. Each aryl residue can be unsubstitutedor mono- or polysubstituted. The aryl can be bound to the superordinategeneral structure via any desired and possible ring member of the arylresidue. The aryl residues can also be condensed with further sat. or(partially) unsat. cycloalkyl or heterocyclyl, aromatic orheteroaromatic ring systems, which can in turn be unsubstituted or mono-or polysubstituted. Examples of condensed aryl residues arebenzodioxolanyl and benzodioxanyl. Preferably, aryl is selected from thegroup consisting of phenyl, 1-naphthyl, 2-naphthyl, fluorenyl andanthracenyl, each of which can be respectively unsubstituted or mono- orpolysubstituted. A particularly preferred aryl is phenyl, unsubstitutedor mono- or polysubstituted.

The term “heteroaryl” for the purpose of this invention represents a 5-,6-, 8-, 9- or 10-membered cyclic aromatic residue containing at least 1,if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatomsare each selected independently of one another from the group S, N and Oand the heteroaryl residue can be unsubstituted or mono- orpolysubstituted; in the case of substitution on the heteroaryl, thesubstituents can be the same or different and be in any desired andpossible position of the heteroaryl. The binding to the superordinategeneral structure can be carried out via any desired and possible ringmember of the heteroaryl residue if not indicated otherwise. Theheteroaryl can also be part of a bi- or polycyclic system having up to10 ring members, wherein the ring system can be formed with further sat.or (partially) unsat. cycloalkyl or heterocyclyl, aromatic orheteroaromatic ring systems, which can in turn be unsubstituted or mono-or polysubstituted. It is preferable for the heteroaryl residue to beselected from the group consisting of benzofuranyl, benzoimidazolyl,benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl,benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl,quinolinyl, dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl,imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl,isoxazoyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxadiazolyl,phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl,purinyl, phenazinyl, thienyl (thiophenyl), triazolyl, tetrazolyl,thiazolyl, thiadiazolyl and triazinyl.

In relation to the terms “C₁₋₆-alkyl”, “C₃₋₁₀-cycloalkyl”, “3 to7-membered heterocyclyl” and “3 to 10-membered heterocyclyl”, the term“mono- or polysubstituted” refers in the sense of this invention, withrespect to the corresponding residues or groups, to the singlesubstitution or multiple substitution, e.g. disubstitution,trisubstitution, tetrasubstitution, or pentasubstitution, of one or morehydrogen atoms each independently of one another by at least onesubstituent selected from the group consisting of F; Cl; Br; I; NO₂; CN;═O; ═NH; ═N(OH); ═N(O—C₁₋₆-alkyl); CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂;C₁₋₆-alkyl; C(═O)—H; C(═O)—C₁₋₆-alkyl; C(═O)—OH; C(═O)—O—C₁₋₆-alkyl;C(═O)—N(H)(OH); C(═O)—NH₂; C(═O)—N(H)(C₁₋₆-alkyl); C(═O)—N(C₁₋₆-alkyl)₂;C(═N—OH)—H; C(═N—OH)—C₁₋₆-alkyl; C(═N—O—C₁₋₆-alkyl)-H;C(═N—O—C₁₋₆-alkyl)-C₁₋₆-alkyl; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; O—C(═O)—O—C₁₋₆-alkyl;O—(C═O)—N(H)(C₁₋₆-alkyl); O—C(═O)—N(C₁₋₆-alkyl)₂; O—S(═O)₂—C₁₋₆-alkyl;O—S(═O)₂—OH; O—S(═O)₂—O—C₁₋₆-alkyl; O—S(═O)₂—NH₂;O—S(═O)₂—N(H)(C₁₋₆-alkyl); O—S(═O)₂—N(C₁₋₆-alkyl)₂; NH₂;N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl;N(H)—C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—NH₂; N(H)—C(═O)—N(H)(C₁₋₆-alkyl);N(H)—C(═O)—N(C₁₋₆-alkyl)₂; N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—NH₂;N(C₁₋₆-alkyl)-C(═O)—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; N(H)—S(═O)₂—OH;N(H)—S(═O)₂—C₁₋₆-alkyl; N(H)—S(═O)₂—O—C₁₋₆-alkyl; N(H)—S(═O)₂—NH₂;N(H)—S(═O)₂—N(H)(C₁₋₆-alkyl); N(H)—S(═O)₂—N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-S(═O)₂—OH; N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-S(═O)₂—NH₂;N(C₁₋₆-alkyl)-S(═O)₂—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl);S(═O)₂—N(C₁₋₆-alkyl)₂; C₃₋₆-cycloalkyl; 3 to 7 membered heterocyclyl;aryl or heteroaryl. The term “polysubstituted” with respect topolysubstituted residues and groups includes the polysubstitution ofthese residues and groups either on different or on the same atoms, forexample trisubstituted on the same carbon atom, as in the case of CF₃,CH₂CF₃ or 1,1-difluorocyclohexyl, or at various points, as in the caseof CH(OH)—CHCl₂ or 1-chloro-3-fluorocyclohexyl. A substituent can ifappropriate for its part in turn be mono- or polysubstituted. Themultiple substitution can be carried out using the same or usingdifferent substituents.

Preferred substituents of “C₁₋₆-alkyl” are selected from the groupconsisting of F; Cl; Br; CF₃; C(═O)—NH₂; C(═O)—N(H)(C₁₋₆-alkyl);C(═O)—N(C₁₋₆-alkyl)₂; C₃₋₆-cycloalkyl or 3 to 7 membered heterocyclyl;OH; O—C₁₋₆-alkyl; NH₂; N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂;N(H)—C(═O)—C₁₋₆-alkyl; N(H)—S(═O)₂—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl; N(H)—S(═O)₂—NH₂; SH; S—C₁₋₆-alkyl;S(═O)₂ C₁₋₆-alkyl and S(═O)₂—N(H)(C₁₋₆-alkyl).

Preferred substituents of “C₃₋₆-cycloalkyl” and “3 to 7-memberedheterocyclyl” are selected from the group consisting of F; Cl; Br; CF₃;CN; ═O; C₁₋₆-alkyl; C₃₋₆-cycloalkyl or 3 to 7 membered heterocyclyl;CHO; C(═O)—C₁₋₆-alkyl; CO₂H; C(═O)O—C₁₋₆-alkyl; CONH₂;C(═O)NH—C₁₋₆-alkyl; C(═O)N(C₁₋₆-alkyl)₂; OH; O—C₁₋₆-alkyl; OCF₃;O—C(═O)—C₁₋₆-alkyl; NH₂; NH—C₁₋₆-alkyl; N(C₁₋₆-alkyl)₂;NH—C(═O)—C₁₋₆-alkyl; SH; S—C₁₋₆-alkyl; SCF₃; S(═O)₂—C₁₋₆-alkyl;S(═O)₂OH; S(═O)₂O—C₁₋₆-alkyl and S(═O)₂—NH—C₁₋₆-alkyl.

In relation to the terms “aryl” and “heteroaryl”, the term “mono- orpolysubstituted” refers in the sense of this invention, with respect tothe corresponding residues or groups, to the single substitution ormultiple substitution, e.g. disubstitution, trisubstitution,tetrasubstitution, or pentasubstitution, of one or more hydrogen atomseach independently of one another by at least one substituent selectedfrom the group consisting of F; Cl; Br; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl;CFCl₂; C₁₋₆-alkyl; C₃₋₆-cycloalkyl; 3 to 7 membered heterocyclyl; aryl;heteroaryl; aryl, heteroaryl, C₃₋₆-cycloalkyl or 3 to 7 memberedheterocyclyl, each connected via a C₁₋₈-alkylene; C(═O)H;C(═O)—(C₁₋₆-alkyl); C(═O)—(C₃₋₆-cycloalkyl); C(═O)-(3 to 7 memberedheterocyclyl); C(═O)-(aryl); C(═O)-(heteroaryl); C(═O)OH;C(═O)—O(C₁₋₆-alkyl); C(═O)—O(C₃₋₆-cycloalkyl); C(═O)—O(3 to 7 memberedheterocyclyl); C(═O)—O(aryl); C(═O)—O(heteroaryl); C(═O)—NH₂;C(═O)—N(H)(C₁₋₆-alkyl); C(═O)—N(H)(C₃₋₆-cycloalkyl); C(═O)—N(H)(3 to 7membered heterocycloalkyl); C(═O)—N(H)(aryl); C(═O)—N(H)(heteroaryl);C(═O)—N(C₁₋₆-alkyl)₂; C(═O)—N(C₁₋₆-alkyl)(C₃₋₆-cycloalkyl);C(═O)—N(C₁₋₆-alkyl)(3 to 7 membered heterocyclyl);C(═O)—N(C₁₋₆-alkyl)(aryl); C(═O)—N(C₁₋₆-alkyl)(heteroaryl); OH; ═O;O—(C₁₋₆-alkyl); O—(C₃₋₆-cycloalkyl); O-(3 to 7 membered heterocyclyl);O-(aryl); O-(heteroaryl); OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;O—C(═O)—(C₁₋₆-alkyl); O—C(═O)—(C₃₋₆-cycloalkyl); O—C(═O)-(3 to 7membered heterocyclyl); O—C(═O)-(aryl); C(═O)-(heteroaryl); O—C(═O)—NH₂;O—C(═O)—N(H)(C₁₋₆-alkyl); O—C(═O)—N(H)(C₃₋₆-cycloalkyl); O—C(═O)—N(H)(3to 7 membered heterocyclyl); O—C(═O)—N(H)(aryl);O—C(═O)—N(H)(heteroaryl); O—C(═O)—N(C₁₋₆-alkyl)₂;O—C(═O)—N(C₁₋₆-alkyl)(C₃₋₆-cycloalkyl); O—C(═O)—N(C₁₋₆-alkyl)(3 to 7membered heterocyclyl); O—C(═O)—N(C₁₋₆-alkyl)(aryl);O—C(═O)—N(C₁₋₆-alkyl)(heteroaryl); NH₂; N(H)(C₁₋₆-alkyl);N(H)(C₃₋₆-cycloalkyl); N(H)(3 to 7 membered heterocyclyl); N(H)(aryl);N(H)(heteroaryl); N(C₁₋₆-alkyl)₂; N(C₁₋₆-alkyl)(C₃₋₆-cycloalkyl);N(C₁₋₆-alkyl)(3 to 7 membered heterocyclyl); N(C₁₋₆-alkyl) (aryl);N(C₁₋₆-alkyl)(heteroaryl); N(H)—C(═O)—(C₁₋₆-alkyl);N(H)—C(═O)—(C₃₋₆-cycloalkyl); N(H)—C(═O)-(3 to 7 membered heterocyclyl);N(H)—C(═O)-(aryl); N(H)—C(═O)-(heteroaryl);N(C₁₋₆-alkyl)-C(═O)—(C₁₋₆-alkyl); N(C₁₋₆-alkyl)-C(═O)—(C₃₋₆-cycloalkyl);N(C₁₋₆-alkyl)-C(═O)-(3 to 7 membered heterocyclyl);N(C₁₋₆-alkyl)-C(═O)-(aryl); N(C₁₋₆-alkyl)-C(═O)-(heteroaryl);N(H)—S(═O)₂—(C₁₋₆-alkyl); N(H)—S(═O)₂—(C₃₋₆-cycloalkyl); N(H)—S(═O)₂-(3to 7 membered heterocyclyl); N(H)—S(═O)₂-(aryl);N(H)—S(═O)₂-(heteroaryl); N(C₁₋₄-alkyl)-S(═O)₂—(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-S(═O)₂—(C₃₋₆-cycloalkyl); N(C₁₋₆-alkyl)-S(═O)₂-(3 to 7membered heterocyclyl); N(C₁₋₆-alkyl)-S(═O)₂-(aryl);N(C₁₋₆-alkyl)-S(═O)₂-(heteroaryl); N(H)—C(═O)—O(C₁₋₆-alkyl);N(H)—C(═O)—O(C₃₋₆-cycloalkyl); N(H)—C(═O)—O(3 to 7 memberedheterocyclyl); N(H)—C(═O)—O(aryl); N(H)—C(═O)—O(heteroaryl);N(C₁₋₆-alkyl)-C(═O)—O(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-C(═O)—O(C₃₋₆-cycloalkyl); N(C₁₋₆-alkyl)-C(═O)—O(3 to 7membered heterocyclyl); N(C₁₋₆-alkyl)-C(═O)—O(aryl);N(C₁₋₆-alkyl)-C(═O)—O(heteroaryl); N(H)—C(═O)—NH₂;N(H)—C(═O)—N(H)(C₁₋₆-alkyl); N(H)—C(═O)—N(H)(C₃₋₆-cycloalkyl);N(H)—C(═O)—N(H)(3 to 7 membered heterocyclyl); N(H)—C(═O)—N(H)(aryl);N(H)—C(═O)—N(H)(heteroaryl); N(C₁₋₆-alkyl)-C(═O)—NH₂;N(C₁₋₆-alkyl)-C(═O)—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-C(═O)—N(H)(C₃₋₆-cycloalkyl); N(C₁₋₆-alkyl)-C(═O)—N(H)(3 to7 membered heterocyclyl); N(C₁₋₆-alkyl)-C(═O)—N(H)(aryl);N(C₁₋₆-alkyl)-C(═O)—N(H)(heteroaryl); N(H)—C(═O)—N(C₁₋₆-alkyl)₂;N(H)—C(═O)—N(C₁₋₆-alkyl)(C₃₋₆-cycloalkyl); N(H)—C(═O)—N(C₁₋₆-alkyl)(3 to7 membered heterocyclyl); N(H)—C(═O)—N(C₁₋₆-alkyl)(aryl);N(H)—C(═O)—N(C₁₋₆-alkyl) (heteroaryl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)(C₃₋₆-cycloalkyl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)(3 to 7 membered heterocyclyl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)(aryl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl) heteroaryl); SH; S—(C₁₋₆-alkyl);S—(C₃₋₆-cycloalkyl); S-(3 to 7 membered heterocyclyl); S-(aryl);S-(heteroaryl); SCF₃; S(═O)₂OH; S(═O)—(C₁₋₆-alkyl);S(═O)—(C₃₋₆-cycloalkyl); S(═O)-(3 to 7 membered heterocyclyl);S(═O)-(aryl); S(═O)-(heteroaryl); S(═O)₂—(C₁₋₆-alkyl);S(═O)₂—(C₃₋₆-cycloalkyl); S(═O)₂-(3 to 7 membered heterocyclyl);S(═O)₂-(aryl); S(═O)₂-(heteroaryl); S(═O)₂—O(C₁₋₆-alkyl);S(═O)₂—O(C₃₋₆-cycloalkyl); S(═O)₂—O(3 to 7 membered heterocyclyl);S(═O)₂—O(aryl); S(═O)₂—O(heteroaryl); S(═O)₂—N(H)(C₁₋₆-alkyl);S(═O)₂—N(H)(C₃₋₆-cycloalkyl); S(═O)₂—N(H)(3 to 7 membered heterocyclyl);S(═O)₂—N(H)(aryl); S(═O)₂—N(H)(heteroaryl); S(═O)₂—N(C₁₋₆-alkyl)₂;S(═O)₂—N(C₁₋₆-alkyl)(C₃₋₆-cycloalkyl); S(═O)₂—N(C₁₋₆-alkyl)(3 to 7membered heterocyclyl); S(═O)₂—N(C₁₋₆-alkyl)(aryl);S(═O)₂—N(C₁₋₆-alkyl)(heteroaryl); S(═O)(═NR¹³)—C₃₋₁₀-cycloalkyl;S(═O)(═NR¹³)-(3 to 7 membered heterocyclyl); S(═O)(═NR¹³)-aryl andS(═O)(═NR¹³)-heteroaryl, wherein R¹³ represents H or C₁₋₆-alkyl.

Preferred substituents of “aryl” and “heteroaryl” are selected from thegroup consisting of F; Cl; CF₃; CN; C₁₋₆-alkyl; C(═O)—OH;C(═O)—O—C₁₋₆-alkyl; CO—NH₂; C(═O)—N(H)C₁₋₆-alkyl; C(═O)—N(C₁₋₆-alkyl)₂;OH; O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; OCF₃; OCHF₂; OCH₂F; NH₂;N(H)C₁₋₆-alkyl; N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)C₁₋₆-alkyl; N(H)—S(═O)₂—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-S(═O)₂(C₁₋₆-alkyl); N(H)C(═O)NH₂;N(H)—C(═O)—N(H)C₁₋₆-alkyl; N(H)—C(═O)—N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-C(═O)—NH₂; N(C₁₋₆-alkyl)-C(═O)—N(H)C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; S(═O)₂C₁₋₆-alkyl; S(═O)₂—NH₂;S(═O)₂—N(H)C₁₋₆-alkyl and S(═O)₂—N(C₁₋₆-alkyl)₂.

The compounds according to the invention are defined by substituents,for example by R¹, R² and R³ (1^(st) generation substituents) which arefor their part if appropriate themselves substituted (2^(nd) generationsubstituents). Depending on the definition, these substituents of thesubstituents can for their part be resubstituted (3^(rd) generationsubstituents). If, for example, R¹=a C₁₋₆-alkyl (1^(st) generationsubstituent), then the C₁₋₆-alkyl can for its part be substituted, forexample with a NH—C₁₋₆-alkyl (2^(nd) generation substituent). Thisproduces the functional group R¹═(C₁₋₆-alkyl-NH—C₁₋₆-alkyl). TheNH—C₁₋₆-alkyl can then for its part be resubstituted, for example withCl (3^(rd) generation substituent). Overall, this produces thefunctional group R¹═C₁₋₆-alkyl-NH—C₁₋₆-alkyl, wherein the C₁₋₆-alkyl ofthe NH—C₁₋₆-alkyl is substituted by Cl. However, in a preferredembodiment, the 3^(rd) generation substituents may not be resubstituted,i.e. there are then no 4^(th) generation substituents. If a residueoccurs multiply within a molecule, then this residue can haverespectively different meanings for various substituents: if, forexample, both R¹ and R² denote a 3 to 10 membered heterocyclyl, then the3 to 10 membered heterocyclyl can e.g. represent morpholinyl for R¹ andcan represent piperazinyl for R².

Within the scope of the present invention, the symbols

used in the formulae denotes a link of a corresponding residue to therespective superordinate general structure.

In one embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that m represents 0or 1. Preferably, m represents 1.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that n represents0.

In yet another embodiment of the first aspect of the invention, thecompound according to general formula (I) is characterized in that mrepresents 1 and n represents 0, so the compound is represented bygeneral formula (II),

In a preferred embodiment of the of the first aspect of the invention,the compound according to general formula (I) is characterized in that mrepresents 1, n represents 0, and Y is bond, CH₂ or C(CH₃)₂.

In a particularly preferred embodiment of the of the first aspect of theinvention, the compound according to general formula (I) ischaracterized in that m represents 1, n represents 0 and Y is CH₂,

so the compound is represented by general formula (IIa),

In another particularly preferred embodiment of the first aspect of theinvention, the compound according to general formula (I) ischaracterized in that m represents 1, n represents 0 and Y is bond,

so the compound is represented by general formula (IIb),

In another embodiment of the first aspect of the invention, the compoundaccording to the invention is one diastereomer. Preferably, the compoundaccording to the invention is the cis-diastereomer. Still preferably,the compound according to the invention is the trans-diastereomer.

Thus, one preferred embodiment of the first aspect of the invention ischaracterized in that the compound of general formula (I), (II), (IIa)or (IIb) is one diastereomer.

The cis-diastereomer or the trans-diastereomer may be in the form of asingle enantiomer or in the form of an enantiomeric mixture, preferablyof a racemate.

In yet another embodiment of the first aspect of the invention, thecompound according to the invention is in only one enantiomeric form.Preferably, the compound according to the invention is the racemate ofthe cis-diastereomer (cis-rac) or a single enantiomer of thecis-diastereomer (cis-EN1 or cis-EN2). Still preferably, the compoundaccording to the invention is the racemate of the trans-diastereomer(trans-rac) or a single enantiomer of the trans-diastereomer (trans-EN1or trans-EN2).

Thus, one preferred embodiment of the first aspect of the invention ischaracterized in that the compound of general formula (I), (II), (IIa)or (IIb) is one enantiomer.

In one preferred embodiment of the first aspect of the invention ischaracterized in that the compound of general formula (I), (II), (IIa)or (IIb) is the enantiomer, which exhibits at room temperature and awavelength of 589 nm (Na-D-line) a positive optical rotation indichloromethane or methanol.

In another preferred embodiment of the first aspect of the invention ischaracterized in that the compound of general formula (I), (II), (IIa)or (IIb) is the enantiomer, which exhibits at room temperature and awavelength of 589 nm (Na-D-line) a negative optical rotation indichloromethane or methanol.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that R² representsH, CH₃, C₂H₅, CH₂CH₂CH₃, CH(CH₃)₂, CH₂OH, CH₂OCH₃, CH₂NH₂, CH₂N(H)CH₃ orCH₂N(CH₃)₂.

Preferably, R² represents H, CH₃ or C₂H₅.

In a preferred embodiment, the compound according to formula (I) ischaracterized in that m represents 1, n represents 0, Y is CH₂, and R²represents H, CH₃ or C₂H₅.

In another preferred embodiment, the compound according to formula (I)is characterized in that m represents 1, n represents 0, Y is bond, andR² represents H, CH₃ or C₂H₅.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that R¹ representsH, CH₃, C₂H₅, CH₂CH₂CH₃, CH₂OCH₃ or CH₂N(CH₃)₂.

Preferably, R¹ represents H, CH₃, C₂H₅ or CH₂OCH₃. Particularlypreferred are compounds wherein R¹ represents CH₃.

In a preferred embodiment, the compound according to formula (I) ischaracterized in that m represents 1, n represents 0, Y is CH₂, and R¹represents H, CH₃, C₂H₅ or CH₂OCH₃.

In another preferred embodiment, the compound according to formula (I)is characterized in that m represents 1, n represents 0, Y is bond, andR¹ represents H, CH₃, C₂H₅ or CH₂OCH₃.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that Ar¹ representsphenyl or pyridinyl, substituted by zero or one or two or threesubstituents R⁷.

In preferred embodiment of the first aspect of the invention, thecompound according to general formula (I) is characterized in that Ar¹represents phenyl or pyridinyl, substituted by one or two substituentsR⁷.

Preferably, R⁷ is independently selected from the group consisting of F;Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; C(═O)—C₁₋₆-alkyl; C(═O)—OH;C(═O)—O—C₁₋₆-alkyl; C(═O)—N(H)(OH); C(═O)—NH₂; C(═O)—N(H)(C₁₋₆-alkyl);C(═O)—N(C₁₋₆-alkyl)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;O—C₁₋₆-alkyl; NH₂; N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂;N(H)—C(═O)—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;N(H)—S(═O)₂—C₁₋₆-alkyl; SCF₃; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl;S(═O)₂—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl);S(═O)₂—N(C₁₋₆-alkyl)₂; C₃₋₁₀-cycloalkyl; 3 to 7 membered heterocyclyl;O—C₃₋₁₀-cycloalkyl and O-(3 to 7 membered heterocyclyl).

In yet another embodiment of the first aspect of the invention, thecompound according to general formula (I) is characterized in that Ar¹represents phenyl or pyridinyl, substituted by zero or one or two orthree substituents R⁷,

wherein each R⁷ is independently selected from the group consisting ofF; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; C(═O)—C₁₋₆-alkyl; C(═O)—OH;C(═O)—O—C₁₋₆-alkyl; C(═O)—N(H)(OH); C(═O)—NH₂; C(═O)—N(H)(C₁₋₆-alkyl);C(═O)—N(C₁₋₆-alkyl)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;O—C₁₋₆-alkyl; NH₂; N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂;N(H)—C(═O)—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;N(H)—S(═O)₂—C₁₋₆-alkyl; SCF₃; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl;S(═O)₂—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl);S(═O)₂—N(C₁₋₆-alkyl)₂; C₃₋₁₀-cycloalkyl; 3 to 7 membered heterocyclyl;O—C₃₋₁₀-cycloalkyl and O-(3 to 7 membered heterocyclyl).

Preferably, Ar¹ represents phenyl or 2-pyridinyl.

In another preferred embodiment of the first aspect of the invention,the compound according to general formula (I) is characterized in thatAr¹ represents subformula SF-I

wherein X is CH or N,

-   R¹⁰ is selected from the group consisting of CF₃; CF₂H; CFH₂; OCF₃;    OCF₂H; OCFH₂; cyclopropyl; Ocyclopropyl; CH(CH₃)₂; OCH(CH₃)₂;    C(CH₃)₃ and OC(CH₃)₃; and-   R¹¹ is selected from the group consisting of H; F; Cl; CN; CH₃;    CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂; CH(CH₃)CH₂CH₃; CH₂CH₂CH₂CH₃;    CH₂CH(CH₃)₂; C(CH₃)₃; CF₃; CF₂H; CFH₂; OCF₃; OCH₃; OCH₂CH₃;    OCH(CH₃)₂; S(═O)—CH₃ and S(═O)₂—CH₃.

More preferably, R¹⁰ is CF₃; CF₂H; CFH₂; OCF₃; OCF₂H or OCFH₂. Even morepreferably, R¹⁰ is CF₃ or OCF₃.

In yet another embodiment of the first aspect of the invention, thecompound according to general formula (I) is characterized in that L is—[C(R⁴)₂]—(X)_(y)—[C(R⁴)₂]_(z-),

wherein x is 0, 1 or 2, y is 0 or 1 and z is 0, with the proviso thatx≧y;

each R⁴ is independently selected from the group consisting of H andC₁₋₆-alkyl, or two R⁴ form together with the C-atom connecting them aC₃₋₁₀-cycloalkyl or a 3 to 7 membered heterocyclyl or two R⁴ formtogether with two adjacent C-atoms connecting them a C₃₋₁₀-cycloalkyl ora 3 to 7 membered heterocyclyl,X is selected from the group consisting of O, S, S(O)₂, N(H) orN(C₁₋₆-alkyl).

In a preferred embodiment of the first aspect of the invention, thecompound according to general formula (I) is characterized in that L is—[C(R⁴)₂]—(X)_(y)—[C(R⁴)₂]_(z)—,

wherein z is 0 and the sum (x+y) is 0 or 2.

Preferably, the compound according to general formula (I) ischaracterized in that L is —[C(R⁴)₂]_(x)—(X)_(y)—[C(R⁴)₂]_(z-),

wherein x is 0, 1 or 2, y is 0 or 1 and z is 0, with the proviso thatx≧y;

each R⁴ is independently selected from the group consisting of H andC₁₋₆-alkyl, or two R⁴ form together with the C-atom connecting them aC₃₋₁₀-cycloalkyl, and

X is O.

More preferably, the compound according to general formula (I) ischaracterized in that L is —[C(R⁴)₂]_(x)—(X)_(y)—[C(R⁴)₂]_(z-),

wherein x is 0 or 1, y is 0 or 1 and z is 0, with the proviso that x y;

each R⁴ is independently selected from the group consisting of H andC₁₋₆-alkyl, or two R⁴ form together with the C-atom connecting them aC₃₋₁₀-cycloalkyl, and

X is O.

In a preferred embodiment of the first aspect of the invention, thecompound according to general formula (I) is characterized in that

L is bond (x=y=z=0); CH₂ (x=1; each R⁴═H; y=z=0); CH₂CH₂ (x=2; eachR⁴═H; y=z=0); C(CH₃)₂ (x=2; R⁴═H and R⁴═CH₃; y=z=0); CH₂C(CH₃)₂ (x=2;R⁴═H and R⁴═CH₃; y=z=0); C(CH₃)₂CH₂ (x=1; each R⁴═CH₃; y=z=0); CH(CH₃)(x=1; R⁴═H and R⁴═CH₃; y=z=0); CH₂O (x=1; each R⁴═H; y=1; X═O; z=0);C(CH₃)₂O (x=1; each R⁴═CH₃; y=1; X═O; z=0); CH(CH₃)O(x=1; R⁴═H andR⁴═CH₃; y=1; X═O; z=0);

(x=1; two R⁴ form together with the C-atom connecting them aC₃-cycloalkyl; y=z=0); or

(x=1; two R⁴ form together with the C-atom connecting them aC₃-cycloalkyl; y=1; X═O; z=0).

In case, L contains an oxygen atom, the compound according to theinvention characterized in that the oxygen atom is directly bond to Ar².Therefore, the structural element -L-Ar² is represented by —Ar²(L=bond); —CH₂—Ar²; —C(CH₃)₂—Ar²; —CH(CH₃)—Ar²; —CH₂O—Ar²;—C(CH₃)₂O—Ar²; —CH(CH₃)O—Ar²;

Preferably L is bond, CH₂; C(CH₃)₂; CH₂CH₂; CH₂C(CH₃)₂; C(CH₃)₂CH₂; CH₂Oor C(CH₃)₂O,

more preferably L is bond or CH₂O.

It has been surprisingly found that compounds with Ar² being aheteroaryl moiety have advantageous properties, in particular withrespect to their pharmacokinetic and pharmacodynamics properties.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that Ar² isselected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl and oxadiazolyl.

Preferably, Ar² is selected from the group consisting of 2-pyridinyl,3-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 3-pyrazinyl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,1-methyl-pyrazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl,1,3-oxazol-5-yl, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazoyl-5-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl and 1,3,4-oxadiazol-2-yl.

Preferably, Ar² is selected from the group consisting of 2-pyridinyl,3-pyridinyl, 2-pyrazinyl, 5-pyrimidinyl, 1,2,4-oxadiazol-5-yl and1,3,4-oxadiazol-2-yl.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that Ar² isselected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl and oxadiazolyl, eachsubstituted by zero or one or two substituents R⁸,

wherein each R⁸ is independently selected from the group consisting ofF; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OCF₃; OCF₂H; OCFH₂;O—C₁₋₆-alkyl; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl;C₃₋₁₀-cycloalkyl; 3 to 7 membered heterocyclyl; aryl; heteroaryl;O—C₃₋₁₀-cycloalkyl; O-(3 to 7 membered heterocyclyl); O-aryl;O-heteroaryl; C(═O)—C₃₋₁₀-cycloalkyl; C(═O)-(3 to 7 memberedheterocyclyl); C(═O)-aryl; C(═O)-heteroaryl; S(═O)₂—C₃₋₁₀-cycloalkyl;S(═O)₂-(3 to 7 membered heterocyclyl); S(═O)₂-aryl; S(═O)₂-heteroaryl;S(═O)(═NR¹³)—C₃₋₁₀-cycloalkyl; S(═O)(═NR¹³)-(3 to 7 memberedheterocyclyl); S(═O)(═NR¹³)-aryl and S(═O)(═NR¹³)-heteroaryl, whereinR¹³ represents H or C₁₋₆-alkyl.

Preferably, R⁸ is selected from the group consisting of F; Cl; CN; CH₃;CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂; CH(CH₃)CH₂CH₃; CH₂CH₂CH₂CH₃; CF₃; CF₂H;CFH₂; OCF₃; OCF₂H; OCFH₂; OCH₃; OCH₂CH₃; OCH₂CH₂CH₃; OCH(CH₃)₂;S(═O)CH₃; S(═O)CH₂CH₃; S(═O)₂CH₃; S(═O)₂CH₂CH₃; cyclopropyl;O-cyclopropyl; oxetanyl; 1,1-dioxidothietanyl; (oxetanyl)oxy;(1,1-dioxidothietanyl)oxy; 2-oxopyrrolidin-1-yl; 2-oxopiperidin-1-yl;azetidine-1-carbonyl; pyrrolidine-1-carbonyl; piperidine-1-carbonyl;pyridinyl, pyrimidinyl; (pyridinyl)oxy, (pyrimidinyl)oxy; imidazolyl;triazinyl; pyrazolyl; N-methyl-pyrazolyl; methoxypyridinyl;hydroxypyridinyl; 2-oxopyridinyl;3-oxo-2,3-dihydro-1H-1,2,4-triazol-1-yl.

In yet another embodiment of the first aspect of the invention, thecompound according to general formula (I) is characterized in that Ar²is selected from the group consisting of pyridinyl, pyrazinyl,pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl and oxadiazolyl, eachsubstituted by zero, one or two substituents R⁸,

wherein each R⁸ is selected from the group consisting of F; Cl; CN; CH₃;CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂; CF₃; CF₂H; CFH₂; OCF₃; OCF₂H; OCFH₂; OCH₃;OCH₂CH₃; OCH(CH₃)₂; S(═O)CH₃; S(═O)CH₂CH₃; S(═O)₂CH₃; S(═O)₂CH₂CH₃;cyclopropyl and O-cyclopropyl.

In yet another embodiment of the first aspect of the invention, thecompound according to general formula (I) is characterized in that Ar²is selected from the group consisting of 2-pyridinyl, 3-pyridinyl,3-pyrazinyl, 4-pyrimidinyl, 1-methyl-pyrazol-5-yl, 1,3-oxazol-2-yl,1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl,1,2-oxazoyl-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl and1,3,4-oxadiazol-2-yl, each substituted by zero, one or two substituentsR⁸,

wherein each R⁸ is selected from the group consisting of F; Cl; CN; CH₃;CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂; CF₃; CF₂H; CFH₂; OCF₃; OCF₂H; OCFH₂; OCH₃;OCH₂CH₃; OCH(CH₃)₂; S(═O)CH₃; S(═O)CH₂CH₃; S(═O)₂CH₃; S(═O)₂CH₂CH₃;cyclopropyl and O-cyclopropyl.

In another particularly preferred embodiment of the first aspect of theinvention, the compound according to general formula (I) ischaracterized in that

m represents 1, n represents 0, Y is CH₂;

R¹ represents H, CH₃, C₂H₅ or CH₂OCH₃;

R² represents H, CH₃ or C₂H₅;

Ar¹ represents subformula SF-I,

wherein X is CH or N,

-   R¹⁰ is selected from the group consisting of CF₃; CF₂H; CFH₂; OCF₃;    OCF₂H and OCFH₂; and-   R¹¹ is selected from the group consisting of H; F; Cl; CN; CH₃;    CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂; CH(CH₃)CH₂CH₃; CH₂CH₂CH₂CH₃;    CH₂CH(CH₃)₂; C(CH₃)₃; CF₃; CF₂H; CFH₂; OCF₃; OCH₃; OCH₂CH₃;    OCH(CH₃)₂; S(═O)—CH₃ and S(═O)₂—CH₃;-   L is bond; and-   Ar² is selected from the group consisting of pyridinyl, pyrazinyl,    pyridazinyl, pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl and    oxadiazolyl, each substituted by zero or one or two substituents R⁸,    -   wherein each R⁸ is independently selected from the group        consisting of F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OCF₃;        OCF₂H; OCFH₂; O—C₁₋₆-alkyl; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl;        S(═O)₂—C₁₋₆-alkyl; C₃₋₁₀-cycloalkyl; 3 to 7 membered        heterocyclyl; aryl; heteroaryl; O—C₃₋₁₀-cycloalkyl; O-(3 to 7        membered heterocyclyl); O-aryl; O-heteroaryl;        C(═O)—C₃₋₁₀-cycloalkyl; C(═O)-(3 to 7 membered heterocyclyl);        C(═O)-aryl; C(═O)-heteroaryl; S(═O)₂—C₃₋₁₀-cycloalkyl; S(═O)₂-(3        to 7 membered heterocyclyl); S(═O)₂-aryl; S(═O)₂-heteroaryl;        S(═O)(═NR¹³)—C₃₋₁₀-cycloalkyl; S(═O)(═NR¹³)-(3 to 7 membered        heterocyclyl); S(═O)(═NR¹³)-aryl and S(═O)(═NR¹³)-heteroaryl,        wherein R¹³ represents H or C₁₋₆-alkyl.

In another particularly preferred embodiment of the first aspect of theinvention, the compound according to general formula (I) ischaracterized in that

-   m represents 1, n represents 0, Y is bond;-   R¹ represents H, CH₃, C₂H₅ or CH₂OCH₃;-   R² represents H, CH₃ or C₂H₅;-   Ar¹ represents subformula SF-I,

wherein X is CH or N,R¹⁰ is selected from the group consisting of CF₃; CF₂H; CFH₂; OCF₃;OCF₂H and OCFH₂; and

-   R¹¹ is selected from the group consisting of H; F; Cl; CN; CH₃;    CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂; CH(CH₃)CH₂CH₃; CH₂CH₂CH₂CH₃;    CH₂CH(CH₃)₂; C(CH₃)₃; CF₃; CF₂H; CFH₂; OCF₃; OCH₃; OCH₂CH₃;    OCH(CH₃)₂; S(═O)—CH₃ and S(═O)₂—CH₃;-   L is bond; and-   Ar² is selected from the group consisting of pyridinyl, pyrazinyl,    pyridazinyl, pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl and    oxadiazolyl, each substituted by zero or one or two substituents R⁸,    -   wherein each R⁸ is independently selected from the group        consisting of F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OCF₃;        OCF₂H; OCFH₂; O—C₁₋₆-alkyl; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl;        S(═O)₂—C₁₋₆-alkyl; C₃₋₁₀-cycloalkyl; 3 to 7 membered        heterocyclyl; aryl; heteroaryl; O—C₃₋₁₀-cycloalkyl; O-(3 to 7        membered heterocyclyl); O-aryl; O-heteroaryl;        C(═O)—C₃₋₁₀-cycloalkyl; C(═O)-(3 to 7 membered heterocyclyl);        C(═O)-aryl; C(═O)-heteroaryl; S(═O)₂—C₃₋₁₀-cycloalkyl; S(═O)₂-(3        to 7 membered heterocyclyl); S(═O)₂-aryl; S(═O)₂-heteroaryl;        S(═O)(═NR¹³)—C₃₋₁₀-cycloalkyl; S(═O)(═NR¹³)-(3 to 7 membered        heterocyclyl); S(═O)(═NR¹³)-aryl and S(═O)(═NR¹³)-heteroaryl,        wherein R¹³ represents H or C₁₋₆-alkyl.

In yet another particularly preferred embodiment of the first aspect ofthe invention, the compound according to general formula (I) ischaracterized in that

-   m represents 1, n represents 0, Y is bond or CH₂;-   R¹ represents H, CH₃, C₂H₅ or CH₂OCH₃;-   R² represents H, CH₃ or C₂H₅;-   Ar¹ represents subformula SF-I,

wherein X is CH or N,

-   R¹⁰ is selected from the group consisting of CF₃; CF₂H; CFH₂; OCF₃;    OCF₂H and OCFH₂; and-   R¹¹ is selected from the group consisting of H; F; Cl; CN; CH₃;    CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂; CH(CH₃)CH₂CH₃; CH₂CH₂CH₂CH₃;    CH₂CH(CH₃)₂; C(CH₃)₃; CF₃; CF₂H; CFH₂; OCF₃; OCH₃; OCH₂CH₃;    OCH(CH₃)₂; S(═O)—CH₃ and S(═O)₂—CH₃;-   L is bond; and-   Ar² is selected from the group consisting of pyridinyl, pyrazinyl,    pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl and oxadiazolyl, each    substituted by zero, one or two substituents R⁸,    wherein each R⁸ is selected from the group consisting of F; Cl; CN;    CH₃; CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂; CF₃; CF₂H; CFH₂; OCF₃; OCF₂H;    OCFH₂; OCH₃; OCH₂CH₃; OCH(CH₃)₂; S(═O)CH₃; S(═O)CH₂CH₃; S(═O)₂CH₃;    S(═O)₂CH₂CH₃; cyclopropyl and O-cyclopropyl.

Particularly preferred compounds according to the invention are selectedfrom the group consisting of

-   1    3-Methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   2    5-Cyclopropyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   3    5-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   4    2-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine-   5    5-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-[1,2,4]oxadiazole-   6    3-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole-   7    2-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine-   8    2-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole-   9    2-Isopropoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   10    2-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-methyl-pyridine-   11    5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyrimidine-   12    2-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine-   13    3-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-methyl-pyridine-   14    5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyridine-   15    3-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2,6-dimethyl-pyridine-   16    2-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-methyl-pyridine-   17    3-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   18    2-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine-   19    5-Cyclopropyl-3-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole-   20    2-Methyl-5-[[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-pyridine-   21    3-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine-   22    2-Cyclopropyl-5-[[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-pyridine-   23    3-Fluoro-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   24    2-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-[1,3,4]oxadiazole-   25    2-(Difluoro-methyl)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole-   26    2-Isopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole-   27    2-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole-   28    3-Chloro-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   29    2-Cyclopropyl-5-[[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-meth    oxy]-pyrazine-   30    3-Chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)pyridine-   31 3-M    ethyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)pyridine-   32    4-Cyclopropyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-oxazole-   33    5-[[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-2-(trifluoromethyl)-pyridine-   34    2-[4-Methyl-4-[(3-methylsulfonyl-phenyl)sulfonyl]-tetrahydro-pyran-2-yl]-3-methyl-sulfonyl-5-(trifluoromethyl)-pyridine-   35    2-[4-[[3-(Difluoro-methyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methylsulfonyl-5-(trifluoromethyl)-pyridine-   36    3-Chloro-2-[4-[[3-fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine-   37    3-Chloro-2-[4-[[3-(difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine-   38    3-Chloro-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   39    3-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine-   40    5-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-pyridine-   41    3-Methoxy-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   42    5-Chloro-3-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   43    3-(Methylsulfinyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine-   44    3-Chloro-5-(methylsulfinyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   45    3-Chloro-5-(difluoro-methyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   46    5-Cyclopropyl-3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole-   47    2-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-[1,3,4]oxadiazole-   48    5-Chloro-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   49    2,4-Dimethoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   50    2-Methoxy-4-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   51    2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-4-ol-   52    4-(Difluoro-methoxy)-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   53    3-Fluoro-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   54    4-Fluoro-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   55    2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-isonicotinonitrile-   56    3-Methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   57    3-Chloro-2-[4-[[3-(difluoro-methyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine-   58    5-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylsulfonyl)pyridine-   59    3-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine-   60    3-cyclopropyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine-   61    Dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine-   62    2-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine-   63    2,6-Dimethyl-3-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   64    2-Methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   65    2-Bromo-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   67    2-Isopropoxy-5-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   68    3-Chloro-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine-   69    2-Methyl-6-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   70    2-(Trifluoromethyl)-5-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   71    1-Methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-1H-pyrazole-   72    2-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   74    2-(Trifluoromethyl)-6-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   75    2-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-(trifluoromethyl)-pyridine-   76    2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   77    3-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine-   78    5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-pyrrolidin-1-yl-pyridine-   79    5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(1H-[1,2,4]triazol-1-yl)-pyridine-   80    2-(2-Methoxy-ethoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   81 Methyl-[5-[4-methyl-4-[[3-(trifluoro    methyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]amine-   82    2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine-   83    Dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidin-2-yl]amine-   84    2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine-   85    2-(Difluoro-methoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   86    Dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazin-2-yl]amine-   87    5-Methoxy-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine-   88    3-Chloro-5-cyclopropyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   89    3-Chloro-5-(difluoro-methoxy)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   90    1-Methyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole-   91    3-Cyclopropyl-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole-   92    3-Chloro-2-[4-[[3-(difluoro-methoxy)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine-   93    3-Chloro-2-[4-[(3-chlorophenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methyl-sulfonyl-pyridine-   94    3-Methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   95    2-[4-[[3-(Difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridine-   96    2-[4-[[3-Fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridine-   97    3-Chloro-2-[4-[(3-isopropyl-phenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine-   98    3-Methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine-   99    3-[[2-(3-Chloro-5-methylsulfonyl-pyridin-2-yl)-4-methyl-tetrahydro-pyran-4-yl]sulfonyl]-benzonitrile-   100    [(5-Methyl-isoxazol-3-yl)-methyl]-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine-   101    7-[5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-2-oxa-7-azaspiro[3.5]nonane-   102    2-[Methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]amino]-ethanol-   103    [(5-Methyl-isoxazol-3-yl)-methyl]-[6-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine-   104    7-[6-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-2-oxa-7-azaspiro[3.5]nonane-   105    [6-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-tetra    hydro-pyran-4-yl-amine-   106    2-[Methyl-[6-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]amino]-ethanol-   107    2-[Methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amino]-ethanol-   108    Cyclopropyl-[6-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine-   109    1-Ethyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole-   110    3-(Difluoro-methoxy)-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole    optionally in the form of a single stereoisomer or a mixture of    stereoisomers, in the form of the free compound and/or a    physiologically acceptable salt or solvate thereof.

Further preferred compounds of the first aspect of the invention arecompounds according to formula (IIc),

wherein R¹, Ar¹ and Ar² are defined as above. The preferred embodimentsfor R¹, Ar¹ and Ar² apply mutatis mutandis.

Further preferred compounds of the invention have formula (IIc), whereinR¹, Ar¹ and Ar² are represented as in the table given below:

Example No Ar¹ R¹ Ar² 111

CH₃

112

CH₃

113

CH₃

114

CH₃

115

CH₃

116

CH₃

117

CH₃

118

CH₃

119

CH₃

120

CH₃

121

CH₃

122

CH₃

123

CH₃

124

CH₃

125

CH₃

126

CH₃

127

CH₃

128

CH₃

129

CH₃

130

CH₃

131

CH₃

132

CH₃

133

CH₃

134

CH₃

135

CH₃

136

CH₃

137

CH₃

138

CH₃

Within the scope of the invention, it is understood that the compoundsaccording the aforesaid list may be in the form of a single stereoisomeror any mixture of stereoisomers.

For instance, the given compound3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 1),

represents

-   cis-rac-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine,

-   [(2R,4S) and    (2S,4R)-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine],    and-   trans-rac-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine,

-   [(2S,4S) and    (2R,4R)-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine],    as well as each individual stereoisomer or any other mixture    thereof.

Furthermore, preference may be given to compounds according to theinvention that cause at least a 50% inhibition, which is present at aconcentration of 3 μM, in a fluorescent assay for CaV2.2 channels withHEK293 cells in which human CaV2.2 channels were stably expressed at aconcentration of less 3 μM, preferably less than 1000 nM, particularlypreferably less than 300 nM, most particularly preferably less than 100nM, even more preferably less than 75 nM, additionally preferably lessthan 50 nM, most preferably less than 10 nM.

In the process, the Ca²⁺ influx is quantified in the FLIPR assay withthe aid of a Ca²⁺-sensitive dye (type Fluo-4, Molecular Probes EuropeBV, Leiden, the Netherlands) in a fluorescent imaging plate reader(FLIPR 3, Molecular Devices, Sunnyvale, USA), as described hereinafter.

The present invention further relates to a compound according to thepresent invention for CaV2.2 calcium channel regulation, preferably foruse in CaV2.2 calcium channel blockage. The present invention thereforefurther relates to a compound according to the present invention for theprophylaxis and/or treatment of disorders and/or diseases which aremediated, at least in part, at least in part, by CaV2.2 channels. Theterm “disorders and/or diseases which are mediated, at least in part, byCaV2.2 channels”, is intended to include each of or all of the diseasestates.

In another aspect of the present invention, the invention therefore alsoprovides pharmaceutical compositions, containing at least one compoundaccording to the invention and optionally one or more suitable,pharmaceutically compatible auxiliaries and/or, if appropriate, one ormore further pharmacologically active compounds.

The pharmaceutical composition according to the invention may be foundas a liquid, semisolid or solid pharmaceutical form, for example in theform of injection solutions, drops, juices, syrups, sprays, suspensions,tablets, patches, capsules, plasters, suppositories, ointments, creams,lotions, gels, emulsions, aerosols or in multiparticulate form, forexample in the form of pellets or granules, if appropriate pressed intotablets, decanted in capsules or suspended in a liquid, and also beadministered as much.

In addition to at least one compound according to the invention, ifappropriate in the form of one of its pure stereoisomers, in particularenantiomers or diastereomers, its racemate or in the form of mixtures ofthe stereoisomers, in particular the enantiomers or diastereomers, inany desired mixing ratio, or if appropriate in the form of acorresponding salt or respectively in the form of a correspondingsolvate, the pharmaceutical composition according to the inventionconventionally contains further physiologically compatiblepharmaceutical auxiliaries which can for example be selected from thegroup consisting of excipients, fillers, solvents, diluents,surface-active substances, dyes, preservatives, blasting agents, slipadditives, lubricants, aromas and binders.

The selection of the physiologically compatible auxiliaries and also theamounts thereof to be used depend on whether the pharmaceuticalcomposition is to be applied orally, subcutaneously, parenterally,intravenously, intraperitoneally, intradermally, intramuscularly,intranasally, buccally, rectally or locally, for example to infectionsof the skin, the mucous membranes and of the eyes. Preparations in theform of tablets, dragées, capsules, granules, pellets, drops, juices andsyrups are preferably suitable for oral application; solutions,suspensions, easily reconstitutable dry preparations and also sprays arepreferably suitable for parenteral, topical and inhalative application.The compounds according to the invention used in the pharmaceuticalcomposition according to the invention in a repository in dissolved formor in a plaster, agents promoting skin penetration being added ifappropriate, are suitable percutaneous application preparations. Orallyor percutaneously applicable preparation forms can release therespective compound according to the invention also in a delayed manner.

The pharmaceutical compositions according to the invention are preparedwith the aid of conventional means, devices, methods and process knownin the art. The amount to be administered to the patient of therespective compounds according to the invention of the above-indicatedgeneral formula I may vary and is for example dependent on the patient'sweight or age and also on the type of application, the indication andthe severity of the disorder. Conventionally 0.001 to 100 mg/kg,preferably 0.05 to 75 mg/kg, particularly preferably 0.05 to 50 mg of atleast one such compound according to the invention are applied per kg ofthe patient's body weight.

CaV2.2 channels are believed to be involved in a variety of diseases ordisorders in mammals such as humans. These include pain (e.g.; acutepain, chronic pain, visceral pain, headache pain, inflammatory pain,mixed pain), stroke (the neuronal damage resulting from head trauma),epilepsy, mood disorders, schizophrenia, neurodegenerative disorders.

Another embodiment of the present invention is at least one compoundaccording the present invention for the treatment and/or prophylaxis ofone or more disorders selected from the group consisting of pain,preferably pain selected from the group consisting of acute pain,chronic pain, visceral pain, headache pain, inflammatory pain and mixedpain; stroke (the neuronal damage resulting from head trauma); mooddisorders; epilepsy; schizophrenia, and neurodegenerative disorders.

Another embodiment of the present invention is at least one compoundaccording to the present invention for the treatment and/or prophylaxisof pain, in particular acute pain and/or chronic pain and/or visceralpain and/or headache pain and/or inflammatory pain and/or mixed pain.Acute pain according to the invention might include nociceptive pain andpost-operative or surgical pain. Chronic pain according to the inventionmight include peripheral neuropathic pain such as post-herpeticneuralgia, traumatic nerve injury, nerve compression or entrapment,small fibre neuropathy, diabetic neuropathy, neuropathic cancer pain,failed back surgery Syndrome, trigeminal neuralgia, phantom limb pain;neuroma pain, complex regional pain syndrome, chronic arthritic pain andrelated neuralgias, and pain associated with cancer, chemotherapy, HIVand HIV treatment-induced neuropathy; central neuropathic pain such asmultiple sclerosis related pain, Parkinson disease related pain,post-stroke pain, post-traumatic spinal cord injury pain, and pain indementia; musculoskeletal pain such as osteoarthritic pain andfibromyalgia syndrome. In treating osteoarthritic pain, joint mobilitywill also improve as the underlying chronic pain is reduced. Thus, atleast one compound for treatment of osteoarthritic pain inherently willalso improve joint mobility in patients suffering from osteoarthritis.Visceral pain according to the invention might include interstitialcystitis, irritable bowel syndrome, Crohn's disease and chronic pelvicpain syndrome. Inflammatory pain according to the invention mightinclude rheumatoid arthritis and endometriosis. Headachepain accordingto the invention might include migraine, cluster headache, tensionheadache syndrome, facial pain and headache caused by other diseases.Mixed pain according to the invention might include lower back pain,neck and shoulder pain, burning mouth syndrome and complex regional painsyndrome.

In another embodiment of the invention, at least one compound accordingto the present invention is particularly suitable for the treatmentand/or prophylaxis of mood disorders. Mood disorders according to theinvention might include anxiety disorder, social anxiety disorder, panicdisorder, specific phobias, for example, specific animal phobias, socialphobias, obsessive-compulsive disorder, agoraphobia, post-traumaticstress syndrome, addiction (including dependence, withdrawal and/orrelapse of medication, including opioids, but also drugs such ascocaine, opioids, alcohol and nicotine), generalised anxiety disorders,single episodic or recurrent major depressive disorders and dysthymicdisorders, or bipolar disorders, for example, bipolar I disorder,bipolar II disorder and cyclothymic disorder.

In another embodiment of the invention, at least one compound accordingto the present invention is particularly suitable for the treatmentand/or prophylaxis of epilepsy. Epilepsy according to the inventionmight include partial seizures such as temporal lobe epilepsy, absenceseizures generalized seizures, and tonic/clonic seizures.

In yet another embodiment of the invention, at least one compoundaccording to the present invention is particularly suitable for thetreatment and/or prophylaxis of neurodegenerative disorders.Neurodegenerative disorders according to the invention might includeParkinson's disease, Alzheimer's disease, multiple sclerosis,neuropathies, Huntington's disease, presbycusis and amyotrophic lateralsclerosis (ALS).

Particularly preferably, at least one compound according to the presentinvention is suitable for the treatment and/or prophylaxis of one ormore disorders and/or diseases selected from the group consisting ofpain, preferably of pain selected from the group consisting of acutepain, chronic pain, visceral pain, headache pain, inflammatory pain andmixed pain; migraine; depression; neurodegenerative diseases, preferablyselected from the group consisting of multiple sclerosis, Alzheimer'sdisease, Parkinson's disease and Huntington's disease; cognitivedysfunctions, preferably cognitive deficiency states, particularlypreferably memory disorders; medication dependency; misuse ofmedication; withdrawal symptoms in medication dependency; development oftolerance to medication, preferably development of tolerance to naturalor synthetic opioids; drug dependency; misuse of drugs; withdrawalsymptoms in drug dependency; alcohol dependency; misuse of alcohol andwithdrawal symptoms in alcohol dependency.

Another embodiment of the present invention therefore relates to use ofat least one compound according to the present invention for thepreparation of a pharmaceutical composition for the treatment and/orprophylaxis of one or more disorders or diseases, particularly selectedfrom the group consisting of pain, preferably pain selected from thegroup consisting of acute pain, chronic pain, visceral pain, headachepain, inflammatory pain and mixed pain; stroke; mood disorders;epilepsy; schizophrenia, and neurodegenerative disorders.

Another aspect of the present invention is a method of treatment and/orprophylaxis of disorders and/or diseases in a mammal, preferably ofdisorders and/or diseases selected from the group consisting of pain,preferably pain selected from the group consisting of acute pain,chronic pain, visceral pain, headache pain, inflammatory pain and mixedpain; stroke; mood disorders; epilepsy; schizophrenia, andneurodegenerative disorders, which comprises administering an effectiveamount of at least one compound according to the present invention tothe mammal.

All preferred embodiments of the first aspect of the invention arepreferred vice versa for the other aspects and embodiments.

The effectiveness against pain can be shown, for example, in the Bennettor Chung model (Bennett, G. J. and Xie, Y. K., A peripheralmononeuropathy in rat that produces disorders of pain sensation likethose seen in man, Pain 1988, 33(1), 87-107; Kim, S. H. and Chung, J.M., An experimental model for peripheral neuropathy produced bysegmental spinal nerve ligation in the rat, Pain 1992, 50(3), 355-363),by tail flick experiments (e.g. according to D'Amour and Smith (J.Pharm. Exp. Ther. 72, 74-79 (1941)) or by the formalin test (e.g.according to D. Dubuisson et al., Pain 1977, 4, 161-174).

EXAMPLES

The compounds according to the invention can be prepared in the mannerdescribed below. The following examples further illustrate the inventionbut are not to be construed as limiting its scope.

All starting materials which are not explicitly described were eithercommercially available (the details of suppliers such as for exampleAcros, Avocado, Aldrich, Apollo, Bachem, Fluka, FluoroChem, Lancaster,Manchester Organics, MatrixScientific, Maybridge, Merck, Rovathin,Sigma, TCI, Oakwood, etc. can be found in the Symyx® Available ChemicalsDatabase of MDL, San Ramon, US or the SciFinder® Database of the ACS,Washington D.C., US, respectively, for example) or the synthesis thereofhas already been described precisely in the specialist literature(experimental guidelines can be found in the Reaxys® Database ofElsevier, Amsterdam, NL or the SciFinder® Database of the ACS,Washington D.C., US, respectively, for example) or can be prepared usingthe conventional methods known to the person skilled in the art.

The reactions were, if necessary, carried out under an inert atmosphere(mostly N₂). The number of equivalents of reagents and the amounts ofsolvents employed as well as the reaction temperatures and times canvary slightly between different reactions carried out by analogousmethods. The work-up and purification methods were adapted according tothe characteristic properties of each compound and can vary slightly foranalogous methods. The yields of the compounds prepared are notoptimized.

All the intermediate products and exemplary compounds were analyticallycharacterized by means of ¹H-NMR spectroscopy. In addition, massspectrometry tests (MS, m/z for [M+H]⁺) were carried out for all theexemplary compounds and selected intermediate products.

The indication “equivalents” (“eq.” or “eq” or “equiv.”) means molarequivalents, “RT” or “rt” means room temperature T (23±7° C.), “M” areindications of concentration in mol/l, “aq.” means aq., “sat.” meanssat., “sol.” means solution, “conc.” means concentrated and “anhydr.”means anhydr. The mixing ratios of solvents are usually stated in thevolume/volume ratio.

Further Abbreviations:

CC=column chromatography; COSY=correlation spectroscopy; d=day(s);DCE=1,2-dichloroethane; DCM=dichloromethane;DIPEA=N,N-diisopropylethylamine; DMF=N,N-dimethylformamide;EDC.HCl=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride;ee=enantiomeric excess; Et₂O=diethyl ether; EtOAc=ethyl acetate;EtOH=ethanol; h=hour(s); HMBC=heteronuclear multiple-bond correlationspectroscopy; HMQC=heteronuclear multiple quantum coherencespectroscopy; HOBt=1-hydroxybenzotriazole; KOt-Bu=potassiumtert-butoxide; LiHMDS=Lithium hexymethyldisilazide; min=minute(s);MeCN=acetonitrile; MeOH=methanol; MS=methanesulfonyl; NOE=NuclearOverhauser Effect; NOESY=Nuclear Overhauser effect spectroscopy;PE=petroleum ether; RM=reaction mixture; TEA=triethylamine;TFA=trifluoroacetic acid; THF=tetrahydrofuran.

Instruments:

¹H-NMR-spectra (including NOESYs) were recorded at 400 MHz on a BrukerAvance-400 spectrometer or on Agilent 300 & 400 MHz spectrometer.

Analytical chiral HPLCs were measured on:

Agilent 1260 Quart. Pump: G1311C, autosampler, ColCom, DAD: AgilentG4212B or

Waters 2695 separation module Detector 2996 & Agilent 1200 series with G1315B detector

Preparative HPLC were performed on:

Waters 2545 Quaternary gradient module with Autosampler2707 & Waters2545

Quaternary gradient module with Manual mode.

Analytical SFC were performed on Thar SFC analytical.

Preparative SFC were performed THAR-SFC 80.

Instruments employed for chiral separations:

Fraction Collector: Gilson 215 Liquid Handler; HPLC instrument modules:Shimadzu LC8-A preparative pumps, Shimadzu SCL-10Avp system controller,Shimadzu SPD-10Avp UV-VIS detector.

Synthesis of Example compounds2-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(Example 4)

2-(5-(Trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol

To a stirred solution of but-3-en-1-ol (1.2 g, 17.1 mmol, 1.0 eq) in DCE(80 mL) and TFA (24 mL, 308 mmol, 18 eq),5-(trifluoromethyl)picolinaldehyde (3.0 g, 17.1 mmol, 1 eq) was addedand the mixture was stirred for 72 h. After completion of the reactionit was quenched with ice water, basified with NaOH and extracted withDCM. The organic layer was dried over anhydr. Na₂SO₄, filtered andevaporated under reduced pressure to give yellow oil. The residue wasdissolved in MeOH (50 mL) and LiOH (1.2 g, 51.3 mmol, 3.0 eq) was addedat RT and the mixture was stirred for 2 h until no evidence of the esterremained. The RM was evaporated to dryness and dissolved in DCM anddried over anhydr. Na₂SO₄ to give crude product which was furtherpurified by CC to afford2-(5-(trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol (1.5 g,36%).

2-(5-(Trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

Methanesulfonyl chloride (1.76 mlL 18.21 mmol, 1.5 eq) was added to anice-cold solution of2-(5-(trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol (3.0 g, 12.1mmol, 1.0 eq) and TEA (5.0 mL, 3.5 mmol, 3.0 eq) in DCM (50 mL) and theRM was stirred at the same temperature for 2 h. The RM was quenched withH₂O. The aq. layer was extracted with DCM (2×50 mL), combined organiclayer was dried over anhydr. Na₂SO₄, filtered and concentrated underreduced pressure to yield crude product which was purified by CC toafford 2-(5-(trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (3.0 g, 76%).

5-(Trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

K₂CO₃ (2.5 g, 18.5 mmol, 2.0 eq) was added to the solution of2-(5-(trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (3.0 g, 9.2 mmol, 1.0 eq) and3-(trifluoromethyl)benzenethiol (3.3 g, 18.5 mmol, 2.0 eq) in DMF (30mL). The RM was stirred at 60° C. for 12 h. Then the RM was cooled to RTand then quenched with ice. The aq. layer was extracted with EtOAc(2×150 mL). Combined organic layer was dried over anhydr. Na₂SO₄,filtered and concentrated under reduced pressure to yield crude masswhich was then purified by CC to afford5-(trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(3.0 g, 80%).

5-(Trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred ice cold solution of5-(trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)thio)-tetrahydro-2H-pyran-2-yl)pyridine(3.0 g, 7.4 mmol, 1.0 eq) in THF: H₂O (3:1), oxone (13.5 g, 22.1 mmol,3.0 eq) was added and RM was stirred at RT for 4 h. After completion ofthe reaction it was diluted with water and the crude product wasextracted with EtOAc. The combined organic layer was washed with water,sat. brine and dried over anhydr. Na₂SO₄, filtered and evaporated underreduced pressure to get crude product which was further purified by CCto afford5-(trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(3.0 g, 92%) as a white solid).

2-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine

To a stirred solution of5-(trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(1.0 g, 2.3 mmol, 1.0 eq) in dry THF (30 mL), LiHMDS (1 M) (4.55 mL, 4.6mmol, 2.0 eq) was added at −78° C. under Ar and stirred for 30 min.Ethyl iodide (0.7 g, 4.6 mmol, 2.0 eq) was added at the same temperatureand the mixture was stirred for 30 min. The RM was allowed to stir for 1h at RT. The RM was quenched with water and extracted with EtOAc (3×50mL). The combined organic layer was washed with sat. brine and finallydried over anhydr. Na₂SO₄, filtered and the solvent was evaporated underreduced pressure to get crude product which was further purified by CCto afford cis (0.5 g, 47%, yellow solid) and trans isomer (0.45 g, 42%,off white solid) as two diastereomers. The relative configuration (cisor trans) was determined by ¹H-NMR and NOE experiments. cis-isomer(SC-106, SC-108): 1H NMR (400 MHz, DMSO-d₆, δ ppm): 1.01-1.06 (3H),1.64-1.68 (1H), 1.79-1.85 (1H), 1.99-2.09 (3H), 2.16-2.20 (1H),3.74-3.80 (1H), 4.06-4.10 (1H), 4.69-4.72 (1H), 7.63-7.65 (1H),7.92-7.96 (1H), 8.02 (s, 1H), 8.14-8.16 (1H), 8.21-8.23 (1H), 8.93 (s,1H).

On irradiating OCH proton “positive” NOE was observed with ethyl protonsCH₂CH₃. trans-isomer (SC-107, SC-109): 1H NMR (400 MHz, DMSO-d₆, δ ppm):0.79-0.85 (3H), 1.43-1.49 (2H), 1.71-1.77 (1H), 1.95-1.99 (1H),2.04-2.08 (1H), 2.42-2.49 (1H), 4.06-4.10 (1H), 4.28-4.33 (1H),5.26-5.29 (1H), 7.70-7.72 (1H), 7.97-8.01 (1H), 8.13 (s, 1H), 8.23-26(3H), 8.91 (s, 1H).

On irradiating OCH proton “no” NOE was observed with ethyl protons—CH₂CH₃. Enantiomers of cis and trans diastereomers were separated bychiral HPLC using chiral pack AD-H column and Ethanol/DEA: (100/0.1) asmobile phase to obtain two desired cis enantiomers (SC-106 and SC-108)and two trans enantiomers (SC-107 and SC-109).

[cis-EN1] SC-106: (0.186 g, 17.5%, off white solid, cis-EN1)

[cis-EN2] SC-108: (0.164 g, 15.4%, yellow solid, cis-EN2)

[trans-EN1] SC-107: (0.079 g, 7.5%, gummy liquid, trans-EN1)

[trans-EN2] SC-109: (0.148 g, 14.0%, gummy liquid, trans-EN2)

3-Methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 1)

Two enantiomers of cis racemic were separated by chiral HPLC, usingchiral pack 1A column and Methanol/DEA: (100/0.1) as mobile phase toobtain two desired cis enantiomers (SC-100 and SC-101).

[cis-EN1] SC-100: 1^(st) eluted enantiomer

[cis-EN2] SC-101: 2^(nd) eluted enantiomer

5-Cyclopropyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 2)

Two enantiomers of cis racemic were separated by SFC using on a chiralpack OJ-H column to obtain two desired cis enantiomers (SC-102 andSC-103).

[cis-EN1] SC-102: 1^(st) eluted enantiomer

[cis-EN2] SC-103: 2^(nd) eluted enantiomer

5-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 3)

Two enantiomers of cis racemic were separated by chiral HPLC, usingchiral pack-1A column and Hexane/EtOAc/Ethanol/DEA: (50/25/25/0.1) asmobile phase to obtain two desired cis enantiomers (SC-104 and SC-105).

[cis-EN1] SC-104: 1^(st) eluted enantiomer

[cis-EN2] SC-105: 2^(nd) eluted enantiomer

4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-carboxylicacid

Step 1: 4-Oxo-pyran-2-carboxylic acid methyl ester

Comanic acid (50 g, 0.357 mol) was dissolved in MeOH (1 L) and cooled to<10° C. Conc. H₂SO₄ (10 mL) was added dropwise and then the wholerefluxed overnight. The volatiles were concentrated in vacuo and theresidue poured into excess iced water. The mixture was extracted withDCM (3×250 mL). The combined organic layer was washed with NaHCO₃solution, brine, dried (Na₂SO₄) and concentrated in vacuo to yieldcrude, which was triturated with hexane to give 4-oxo-pyran-2-carboxylicacid methyl ester (50 g, 97%) as solid.

Step 2: 4-Hydroxy-tetrahydro-pyran-2-carboxylic acid methyl ester

A solution of 4-oxo-pyran-2-carboxylic acid methyl ester (25 g, 0.162mol) in MeOH (500 mL) was hydrogenated over 10% Pd—C (8 g) overnight at40-50 psi. Filtration and concentration in vacuo gave residue. This waspurified by flash CC (silica gel) by eluting with 0-20% EtOAc in hexane(to remove non-polar impurities) and then with 3-5% MeOH in CHCl₃ toyield 4-hydroxy-tetrahydro-pyran-2-carboxylic acid methyl ester (12.5 g,48%) as an oil.

Step 3: 4-Methylsulfonyloxy-tetrahydro-pyran-2-carboxylic acid methylester

DIPEA (64 mL, 0.37 mol) was added to a solution of4-Hydroxy-tetrahydro-pyran-2-carboxylic acid methyl ester (24 g, 0.15mol) in DCM (240 mL) at 0° C. and MSCI (17.27 g, 0.22 mol) was addeddropwise. The mixture was warmed to RT and stirred overnight. The RM wasdiluted with DCM and washed with iced-water, NaHCO₃ solution, brine,dried (Na₂SO₄) and concentrated in vacuo to yield crude4-methylsulfonyloxy-tetrahydro-pyran-2-carboxylic acid methyl ester (34g) which was taken as such to the next step.

Step 4:4-[[3-(Trifluoromethyl)phenyl]sulfanyl]-tetrahydro-pyran-2-carboxylicacid methyl ester

A solution of 4-methylsulfonyloxy-tetrahydro-pyran-2-carboxylic acidmethyl ester (34 g 0.147 mol) in DMF (340 mL) was treated with3-trifluoromethyl benzene thiol (40 mL, 0.294 mol) and K₂CO₃ (40 g,0.294 mol) at 0° C. The whole was then heated at 50-55° C. for 6 h. Themixture was quenched into iced-water and extracted with EtOAc (5×100mL). The combined filtrate was washed with brine (4×100 mL), dried(Na₂SO₄) and evaporated to dryness. The crude was purified over flash CC(silica gel) by eluting with EtOAc in hexane (10-20%) to afford4-[[3-(trifluoromethyl)phenyl]sulfanyl]tetrahydro-pyran-2-carboxylicacid methyl ester (21 g, 42.8% over 2 steps).

Step 5:[4-[[3-(Trifluoromethyl)phenyl]sulfanyl]-tetrahydro-pyran-2-yl]-methanol

A suspension of LiAlH₄ (0.47 g, 0.012 mol) in dry THF (40 mL) was cooledto <10° C. and a solution of4-[[3-(trifluoromethyl)phenyl]sulfanyl]tetrahydro-pyran-2-carboxylicacid methyl ester (4 g, 0.12 mol) in dry THF (40 mL) was added dropwise.The mixture was stirred at same temperature for 2 h and then quenchedwith sat. NH₄Cl solution. The mixture was then filtered over celite,washed with EtOAc and filtrate was washed with brine, dried (Na₂SO₄) andconcentrated in vacuo to give[4-[[3-(trifluoromethyl)-phenyl]sulfanyl]tetrahydro-pyran-2-yl]-methanol(3.3 g, 90.4%) as oil.

Step 6:2-(Phenylmethoxy-methyl)-4-[[3-(trifluoromethyl)phenyl]sulfanyl]-tetrahydro-pyran

A solution of give[4-[[3-(Trifluoromethyl)phenyl]sulfanyl]-tetrahydro-pyran-2-yl]-methanol(3.3 g, 0.011 mol) in dry THF (33 mL) was added dropwise to a suspensionof NaH (60% in mineral oil; 0.9 g, 0.022 mol) was added to dry THF (33mL) at 0° C. and stirred at same temperature for 30 min. Benzyl bromide(1.34 mL, 0.011 mol) was added and the whole heated at reflux for 4 h.The mixture was cooled to RT, quenched with NH₄Cl solution and extractedwith EtOAc (3×25 mL). The combined organic layer was washed with brine,dried (Na₂SO₄) and concentrated in vacuo to give crude. Purification(silica gel) using 10-15% EtOAc in hexane afforded2-(phenylmethoxy-methyl)-4-[[3-(trifluoromethyl)phenyl]sulfanyl]-tetrahydro-pyran(4.5 g, 96%) as an oil.

Step 7:2-(Phenylmethoxy-methyl)-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran

A solution of oxone (21.7 g, 0.035 mol) in water (110 mL) was addeddropwise to a solution of2-(phenylmethoxy-methyl)-4-[[3-(trifluoromethyl)phenyl]sulfanyl]-tetrahydro-pyran(4.5 g, 0.011 mol) in MeOH (135 mL) at <10° C. and stirred overnight atRT. The RM was concentrated to remove MeOH and diluted with iced-water.Extracted with DCM (3×30 mL); the combined organic layer washed withbrine, dried (Na₂SO₄) and concentrated in vacuo. The crude was purified(silica gel) and compound eluted with 18-22% EtOAc in hexane.Evaporation gave2-(Phenylmethoxy-methyl)-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran(3.7 g, 78%) as an oil.

Step 8:4-Ethyl-2-(phenylmethoxy-methyl)-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran

A solution of KOt-Bu (1 M in THF, 17.8 mL, 0.017 mol) was added dropwiseto a solution of2-(phenylmethoxy-methyl)-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran(3.7 g, 0.009 mol) in dry THF (74 mL) at −78° C. and stirred at sametemperature for 15 min. Ethyl iodide (1.78 mL, 0.022 mol) was added andthe RM stirred at RT for 24 h. The mixture was poured into iced-water,extracted with EtOAc (3×100 mL). The combined organic layer was washedwith water, brine, dried (Na₂SO₄) and concentrated in vacuo to crude.Purification (silica gel) by eluting with 16% EtOAc in hexane gave4-ethyl-2-(phenylmethoxy-methyl)-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran(1.2 g, 30%) as oil.

Step 9:[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methanol

A solution of BBr₃ (1 M in DCM; 0.0054 mol, 5.4 mL) was added dropwiseinto a solution of4-ethyl-2-(phenylmethoxy-methyl)-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran(1.2 g, 0.0027 mol) in DCM (24 mL) at −78° C. and stirred for 3 h atsame temperature. The RM was quenched with MeOH (3 mL) and poured intoiced-water. The organic layer was separated, washed with NaHCO₃solution, water, brine, dried (Na₂SO₄) and concentrated in vacuo tocrude. Purification (silica gel) by eluting with 18% EtOAc in hexanegave[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methanol(750 mg, 79%) as an oil.

Step 10:4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-carboxylicacid

Jones' reagent [0.63 g (0.0063 mol) CrO₃ in H₂SO₄ (1.72 mL) and water(5.6 mL)] was added to a solution of[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methanol(750 mg, 0.0021 mol) in acetone (13 mL) and the whole stirred at 0-5° C.for 6-7 h. Excess reagent was quenched with isopropanol (3 mL) and themixture concentrated in vacuo and residue added to iced-water. Basifiedwith NaHCO₃ solution and filtered. The filtrate was washed with EtOAcand aq. layer acidified with 6 N HCl to pH-2. Extracted with EtOAc (5×25mL), washed with brine, dried (Na₂SO₄) and concentrated to give4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-carboxylicacid (400 mg, 51%) as an oil.

5-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-[1,2,4]oxadiazole(Example 5)

Step 1:4-ethyl-N-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)4-ethyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide

EDC.HCl (1.04 g, 5.46 mmol) and HOBt (0.73 g, 5.46 mmol) were added to astirred solution of4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-carboxylicacid (1 g, 2.73 mmol) in THF (20 mL) at 0° C., stirred for 15 min andadded TEA (0.76 mL, 5.46 mmol) followed by2,2,2-trifluoro-N′-hydroxyacetimidamide (0.35 g, 2.73 mmol). Theresulting RM was allowed to warm to RT and stirred for 16 h. RM wasdiluted with chilled water (40 ml) and extracted with EtOAc (2×100 mL).Combined organic extract was washed with brine solution (50 mL), dried(Na₂SO₄) and concentrated under reduced pressure to get crude4-ethyl-N-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)4-ethyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide(1.2 g, crude) as a thick liquid. Crude was used as such in next stepwithout purification.

Step 2:5-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-[1,2,4]oxadiazole

Sodium acetate (0.56 g, 6.89 mmol) was added to a solution of4-ethyl-N-(2,2,2-trifluoro-1-(hydroxylimino)ethyl)4-ethyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide(1.2 g, 3.44 mmol) in EtOH (12 mL) and water (9.5 mL) mixture andstirred at 80° C. for 16 h. RM mass was concentrated and the residue wasdiluted with DCM (150 mL) and water (50 mL). Organic layer was separatedand washed with brine solution (50 mL), dried (Na₂SO₄) and concentratedunder reduced pressure to get crude. The crude upon purification by CC(silica gel, 0-13% EtOAc in PE) gave5-(4-ethyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1,2,4-oxadiazole(racemic) (0.50 g) as a white solid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.24-8.25 (1H), 8.19-8.20 (1H), 8.06(1H), 7.97-8.00 (1H), 5.16-5.19 (1H), 4.02-4.06 (1H), 3.76-3.81 (1H),2.16-2.27 (2H), 1.94-2.07 (3H), 1.68-1.72 (1H), 1.00-1.02 (3H) ppm.

NOE: C-2 proton & ethyl=cis

Chiral resolution of [cis-rac]5-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-[1,2,4]oxadiazole

[Cis-rac]5-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-[1,2,4]oxadiazole(500 mg) was subjected to preparative chiral-LC (OJ-H-column, 0.1%diethylamine in hexane/EtOH, 9:1). The products were dried to give 105mg of [cis-EN1] SC-200 and 96 mg of [cis-EN2] SC-201.

[cis-EN1] SC-200—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, RT, 0.1% isopropylamine in hexane/EtOH 70/30, Ret. Time 6.08;ee>95%

[cis-EN2] SC-201—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, RT, 0.1% isopropylamine in hexane/EtOH 70/30, Ret. Time 7.31;ee>95%

3-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole(Example 6)

Step 1:N-(cyclopropyl(hydroxyimino)methyl)4-ethyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide

EDC.HCl (1.04 g, 5.46 mmol) and HOBt (0.73 g, 5.46 mmol) were added to astirred solution of4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-carboxylicacid (1 g, 2.73 mmol) in THF (20 mL) at 0° C., stirred for 10 min andadded TEA (0.76 mL, 5.46 mmol) followed by(Z)—N′-hydroxycyclopropanecarboximidamide (0.27 g, 2.73 mmol). Theresulting mixture was allowed to RT and stirred for 16 h. RM was dilutedwith chilled water (40 ml) and extracted with EtOAc (2×100 mL). Combinedorganic extract was washed with brine solution (50 mL), dried (Na₂SO₄)and concentrated under reduced pressure to get crudeN-(cyclopropyl(hydroxyimino)methyl)4-ethyl-4-((3-(trifluoromethyl)-phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide(0.9 g, crude) as a thick liquid.

Step 2:3-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole

Sodium acetate (0.32 g, 4.01 mmol) was added to a solution ofN-(cyclopropyl(hydroxyimino)methyl)-4-ethyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide(0.9 g, 2.00 mmol) in EtOH (10 mL) and water (8 mL) mixture and stirredat 80° C. for 16 h. RM was concentrated and the residue was diluted withDCM (150 mL) and water (50 mL). Organic layer was separated and washedwith brine solution (50 mL), dried (Na₂SO₄) and concentrated underreduced pressure to get crude. The crude upon purification by CC (silicagel, 0-9% EtOAc in PE) gave3-cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole(0.38 g, 44%) as a thick liquid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.23-8.25 (1H), 8.18-8.19 (1H), 8.04(1H), 7.96-7.98 (1H), 4.93-4.95 (1H), 3.96-3.98 (1H), 3.69-3.73 (1H),2.03-2.16 (3H), 1.94-2.02 (3H), 1.66-1.69 (1H), 1.05-1.09 (2H),0.97-1.00 (3H), 0.87-0.90 (2H) ppm.

NOE: C-2 proton & ethyl=cis

Chiral resolution of [cis-rac]3-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole

[Cis-rac]3-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole(380 mg) was subjected to preparative chiral-SFC. The products weredried to give 86 mg of [cis-EN1] SC-202 and 94 mg of [cis-EN2] SC-203.

[cis-EN1] SC-202—analytical chiral SFC: LUX Amylose-2 (250×4.6 mm 5μ), 3g/min, 100 bar, RT, co-solvent: 20% of 0.5% diethylamine in MeOH, Ret.Time 2.12; ee>95%

[cis-EN2]—SC-203—analytical chiral SFC: LUX Amylose-2 (250×4.6 mm 5μ), 3g/min, 100 bar, RT, co-solvent: 20% of 0.5% diethylamine in MeOH, Ret.Time 2.72; ee>95%

2-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine(Example 7)

Step 1:N,N′-(2-(1-dimethylamino)methylidine)-propane-1,3-diylidene)-bis-(N-methylmethanaminium)bis tetrafluoroborate

POCl₃ (27 mL, 345 mmol) was added drop-wise over a period of 90 min toDMF (122 mL, 1.57 mol) at 0° C., and then Bromoacetic acid (15 g, 107mmol) was added and heated to 90° C. for 6 h. DMF was distilled off invacuo and crushed ice was added to the residue. A solution of NaBF₄(23.7 g, 215.8 mmol) in H₂O (60 mL) was then added to the mixture andcooled to −40° C. for 2 h. The precipitated solid was filtered andwashed with EtOAc, then recrystallized in hot MeCN (3 Vol) thrice andthe resulting solid was dried in suction to get crudeN,N′-(2-(1-dimethylamino)methylidine)-propane-1,3-diylidene)-bis-(N-methylmethanaminium)bis tetrafluoroborate (14 g, 36%).

Step 2: 2-cyclopropylpyrimidine-5-carbaldehyde

Sodium methoxide (16.74 g, 310 mmol) was added to a solution ofcyclopropane car-boxamidine HCl (12 g, 124 mmol) in MeOH (150 mL) at−20° C., stirred for 30 min and addedN,N′-(2-(1-dimethylamino)methylidine)-propane-1,3-diylidene)-bis-(N-methylmethanaminium)bis tetrafluoroborate (25 g, 105 mmol) at same temperature and thenwarmed to RT and stirred for 16 h. Solvent was concentrated and theresidue was diluted with chilled water (100 mL) and extracted with DCM(2×150 mL). Combined organic layer was washed with brine (100 mL), dried(Na₂SO₄) and concentrated in vacuo to get crude. Purification by CC(silica gel, 0-30% EtOAc in PE) gave2-cyclopropylpyrimidine-5-carbaldehyde (3 g; 29%) as a solid.

Step 3:2-(2-cyclopropylpyrimidin-5-yl)tetrahydro-2H-pyran-4-ol(4-chloro-2-methylphenyl)tetrahydro-2H-pyran-4-ol

2-cyclopropylpyrimidine-5-carbaldehyde (8 g, 54.05 mmol) was dissolvedin DCE (160 mL), cooled in an ice bath and TFA (64 mL) followed by3-butenol (4.68 mL, 54.05 mmol) were added and stirred at RT for 72 h.The mixture was concentrated in vacuo and the residue diluted with water(100 mL), basified with 6 M NaOH (aq) and extracted with DCM (3×200 mL).Organic layer was separated and washed with brine (50 mL), dried(Na₂SO₄) and concentrated under reduced pressure to get crude. The crudeproduct was dissolved in MeOH (200 mL) and LiOH (6.64 g, 158.22 mmol)was added. The reaction was stirred at RT for 16 h. MeOH wasconcentrated under reduced pressure and the residue was diluted with DCM(200 mL) and washed with water (50 mL), brine (50 mL), dried (Na₂SO₄)and concentrated in vacuo to get crude. Purification by CC (silica gel,0-50% EtOAc in PE) gave2-(2-cyclopropylpyrimidin-5-yl)tetrahydro-2H-pyran-4-ol(4-chloro-2-methylphenyl)tetrahydro-2H-pyran-4-ol(8 g; 67%) as a solid.

Step 4:2-(2-cyclopropylpyrimidin-5-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

Methanesulphonyl chloride (4.26 mL, 54.79 mmol) was added to a solutionof2-(2-cyclopropylpyrimidin-5-yl)tetrahydro-2H-pyran-4-ol(4-chloro-2-methylphenyl)tetrahydro-2H-pyran-4-ol(8 g, 36.52 mmol) and DIPEA (15.97 mL, 91.30 mmol) in DCM (70 mL) at 0°C. and allowed to RT and stirred for 16 h. The RM was diluted with DCM(500 mL) and washed sequentially with sat. NaHCO₃ solution (50 mL),water (50 mL), and brine (50 mL), dried (Na₂SO₄) and concentrated underreduced pressure to get crude2-(2-cyclopropylpyrimidin-5-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate(10 g) as a thick liquid.

Step 5:2-cyclopropyl-5-(4-(3-(trifluoromethyl)phenylthio)tetrahydro-2H-pyran-2yl)pyrimidine

3-Trifluoromethyl thiophenol (13.79 mL, 100.67 mmol) was added to asuspension of2-(2-cyclopropylpyrimidin-5-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate(10 g, 33.55 mmol) and K₂CO₃ (9.25 g, 67.10 mmol) in DMF (100 mL) andthe RM was heated to 50° C. for 5 h and continued at RT for 16 h. Aftercompletion of reaction, the RM was diluted with water (100 mL) andextracted with EtOAc (3×250 mL). Combined organic extract was washedwith water (100 mL), brine (100 mL), dried (Na₂SO₄) and concentratedunder reduced pressure to get crude compound. The crude compound waspurified by CC (silica gel, 0-15% EtOAc in PE) to obtain2-cyclopropyl-5-(4-(3-(trifluoromethyl)phenylthio)tetrahydro-2H-pyran-2yl)pyrimidine(6 g, 44%) as a solid.

Step 6:2-cylopropyl-5-(4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyrimidine

2-Cyclopropyl-5-(4-(3-(trifluoromethyl)phenylthio)tetrahydro-2H-pyran-2yl)pyrimidine(4 g, 10.52 mmol) was dissolved in MeOH (120 mL) and a solution of OXONE(9.69 g, 15.78 mmol) in water (100 mL) was added and stirred at RT for16 h. MeOH was concentrated in vacuo; the residue was diluted with water(50 mL) and extracted with EtOAc (3×150 mL). The organic extract waswashed with brine (50 mL), dried (Na₂SO₄) and concentrated to get crude.The crude compound was purified by CC (silica gel, 0-15% EtOAc in PE) toobtain2-cylopropyl-5-(4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyrimidine(3 g, 69%) as a solid.

Step 7:2-cyclopropyl-5-4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyrimidine

A solution of2-cylopropyl-5-(4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyrimidine(2 g, 4.85 mmol) in THF (40 mL) was cooled to −78° C. and KOt-Bu (1 Msolution in THF; 9.70 mL, 9.70 mmol) was added drop-wise, stirred for 30min, then added methyl iodide (0.75 mL, 12.12 mmol) and the RM wasallowed to RT and stirred for 16 h. The RM was diluted with EtOAc (200mL) and washed with water (50 mL), brine (50 mL), dried over (Na₂SO₄)and concentrated under reduced pressure to get crude compound. The crudecompound was purified by CC (Neutral alumina, 0-15% EtOAc in PE) toobtain2-cyclopropyl-5-4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyrimidine(1 g, 48%) as a white solid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.56 (2H), 8.17-8.22 (2H), 8.06 (1H),7.92-7.96 (1H), 4.59-4.62 (1H), 4.04-4.07 (1H), 3.69-3.73 (1H),2.10-2.22 (2H), 1.94-1.97 (1H), 1.76-1.77 (1H), 1.48-1.52 (4H),0.96-1.05 (4H) ppm.

NOE: C-2 proton & methyl=cis

Chiral resolution of [cis-rac]2-cyclopropyl-5-4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyrimidine

[Cis-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(900 mg) was subjected to preparative chiral-LC (IC-column, hexane/EtOH,7:3). The products were dried to give 113 mg of [cis-EN1] SC-204 and 113mg of [cis-EN2] SC-205.

[cis-EN1] SC-204—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, RT, 0.1% diethylamine in hexane/EtOH 60/40, Ret. Time 6.64;ee>95%

[cis-EN2] SC-205—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, RT, 0.1% diethylamine in hexane/EtOH 60/40, Ret. Time 8.20;ee>95%

2-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole(Example 8)

Chiral resolution of [cis racemic]2-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole

[Cis-rac]2-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazolewas subjected to preparative chiral-SFC (LUX Cellulose-column, 35% MeOH,100 bar, 100 g/min) to give [cis-EN1] SC-206 and [cis-EN2] SC-207.

[cis-EN1] SC-206—analytical chiral SFC: LUX Cellulose (250×4.6 mm 5μ), 3g/min, RT, MeOH 30%, Ret. Time 2.56; ee>95%

[cis-EN2] SC-207—analytical chiral SFC: LUX Cellulose (250×4.6 mm 5μ), 3g/min, RT, MeOH 30%, Ret. Time 3.42; ee>95%

General Reaction Scheme for the Preparation of Examples 9 to 18

2-Isopropoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 9)

Step 1: 2-(6-Isopropoxypyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

MsOH (19.18 mL, 295 mmol) was added dropwise by syringe to a cooled (0°C.) solution of 6-isopropoxynicotinaldehyde (4.88 g, 29.5 mmol) andbut-3-en-1-ol (2.54 mL, 29.5 mmol,) in DCM (40 mL). The RM was stirredat 0° C. for 3 h. The RM was diluted with DCM (60 mL) and, whilestirring vigorously, sat. aq. NaHCO₃ (350 mL) was added. The organicswere separated and the aq. layer was extracted with DCM (2×100 mL). Thecombined organics were dried over Na₂SO₄ and the solvent was removedunder reduced pressure to afford a yellow oil. The product was coatedonto hydromatrix and purified using CC (silica, gradient, heptane/EtOAc,9:1 to 1:1) to give 8.02 g (82%) of the desired product as a pale yellowoil.

Step 2:2-Isopropoxy-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

3-(Trifluoromethyl)benzenethiol (2.403 mL, 18.07 mmol) and K₂CO₃ (2.498g, 18.07 mmol) were added to a N₂ degassed solution of2-(6-isopropoxypyridin-3-yl)tetrahydro-2H-pyran-4-yl methanesulfonate (3g, 9.04 mmol) in MeCN (60 mL) and the RM was stirred for 3 h at 50° C.,more 3-(trifluoromethyl)benzenethiol (1.202 mL, 9.04 mmol), K₂CO₃ (1.249g, 9.04 mmol) and MeCN (40 mL) were added and the RM was stirred at 50°C. for 64 h. The RM was allowed to cool to RT and the solvent wasremoved under reduced pressure. The residue was partitioned between H₂O(150 mL) and EtOAc (150 mL). The aq. layer was extracted with EtOAc(2×100 mL) and the combined organics were washed with brine (100 mL) anddried over Na₂SO₄. The solvent was removed under reduced pressure andthe residue which was coated onto silica and purified using flashchromategraphy (silica, gradient heptane/i-Pr₂O, 1:0-2:1) to give 3.16 g(88%) of the desired product as a yellow oil.

Step 3:2-Isopropoxy-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

A solution of oxone (9.78 g, min. 27.5 mmol) in H₂O (70 mL) was addeddropwise to a cooled (0° C.) solution of2-isopropoxy-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(3.16 g, 7.95 mmol) in MeOH (100 mL) while keeping the internaltemperature below 5° C. The RM was stirred at 0° C. for 1 h andsubsequently for 18 h at RT. The majority of the MeOH was removed underreduced pressure and the residue partitioned between sat. aq. NaHCO₃(100 mL) and EtOAc (100 mL). The aq. layer was extracted with EtOAc(2×50 mL). The organics were combined and washed with brine (100 mL),dried over Na₂SO₄ and concentrated under reduced pressure to afford apale yellow oil that slowly partially crystallised. The product wasdiluted with DCM (10 mL) and purified using flash chromatography(silica, gradient heptane/EtOAc, 1:0-3:1) to afford a colorless oilwhich was co-evaporated with DCM (50 mL) and heptane (50 mL). Theresulting oil slowly solidified into a white solid over the course of 72h. The solids were dried further under reduced pressure to give 3.22 g(94%) of the desired product as a white solid.

Step 4:2-Isopropoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

The glassware was dried under N₂ using a heatgun. 1 M KOt-Bu in THF(3.49 mL, 3.49 mmol) was added dropwise by syringe to a cooled (−78° C.)solution of2-isopropoxy-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(1 g, 2.329 mmol) in dry THF (10 mL). The RM was stirred for 10 min at−78° C. Mel (0.728 mL, 11.64 mmol) was added dropwise by syringe and theRM was stirred for 30 min at −78° C. The RM was quenched by adding sat.aq. NH₄Cl (10 mL) and most of the solvent was removed under reducedpressure. The residue was partitioned between DCM (100 mL) and H₂O (100mL). The aq. layer was extracted with DCM (3×50 mL) and the combinedorganics were concentrated under reduced pressure to give a yellow oilwhich was purified using flash chromatography (silica, gradientheptane/EtOAc, 1:0-7:3) to give 892 mg (86%) of [cis-rac]2-isopropoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineas a colorless oil that slowly crystallised into a white solid.[Trans-rac]2-isopropoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-302 was also obtained and lyophilised using MeCN/H₂O (1/1, v/v, 2 mL)to give 101 mg (10%).

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]2-isopropoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine:δ=8.14 (s, 1H), 8.09-8.00 (m, 2H), 7.95 (d, J=7.8 Hz, 1H), 7.74 (t,J=7.8 Hz, 1H), 7.55 (dd, J=8.6, 2.5 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H),5.27 (hept, J=6.2 Hz, 1H), 4.39 (dd, J=11.5, 1.9 Hz, 1H), 4.14 (dd,J=12.1, 4.2 Hz, 1H), 3.70 (td, J=12.4, 2.1 Hz, 1H), 2.36 (td, J=12.7,5.3 Hz, 1H), 2.22 (t, J=12.3 Hz, 1H), 1.70 (d, J=13.0 Hz, 1H), 1.56-1.51(m, 5H) [overlap with H₂O signal], 1.33 (d, J=6.2 Hz, 6H).

¹H-NMR (400 MHz, CDCl₃) of [trans-rac]2-isopropoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-302: δ=8.19-8.06 (m, 3H), 7.96 (d, J=7.8 Hz, 1H), 7.77 (t, J=7.8 Hz,1H), 7.57 (dd, J=8.6, 2.5 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 5.29 (hept,J=6.2 Hz, 1H), 5.17 (dd, J=11.7, 2.2 Hz, 1H), 4.41 (td, J=12.4, 2.4 Hz,1H), 4.04 (dd, J=11.9, 4.4 Hz, 1H), 2.39 (d, J=15.3 Hz, 1H), 2.33-2.24(m, 1H), 1.83 (ddd, J=15.4, 12.8, 5.7 Hz, 1H), 1.67 (dd, J=15.3, 11.8Hz, 1H), 1.34 (d, J=6.2 Hz, 6H), 1.24 (s, 3H).

The relative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis-rac]2-isopropoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-Pyran-2-yl]-pyridine

[Cis-rac]2-isopropoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(300 mg, 0.676 mmol) was subjected to preparative chiral-LC (IC-column,heptane/EtOH 9:1) and the products were lyophilised using MeCN/H₂O (3/1,v/v, 2 mL) to give 131 mg (44%) of [cis-EN1] SC-300 and 128 mg (43%) of[cis-EN2] SC-301 as white solids.

[cis-EN1] SC-300—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 80/20, Ret. Time 8.337; ee>95%/specificrotation [α]_(D) ^(23.4) −14.1° (c 0.94; DCM).

[cis-EN2] SC-301—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 80/20, Ret. Time 12.064; ee>95%/specificrotation [α]_(D) ^(23.5) +12.7° (c 0.87; DCM).

2-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-methyl-pyridine(Example 10)

The first 3 steps were carried out in analogy to the synthesis of2-isopropoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(steps 1-3).

Step 4:2-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-methyl-pyridine

1M KOt-Bu in THF (11.68 mmol, 11.68 mL) was added dropwise by syringeover the course of 1 h to a cooled (−78° C.) solution of2-methyl-6-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(1.5 g, 3.89 mmol) in dry THF (15 mL) under N₂. After stirring for 10min at −78° C., Etl (1.573 mL, 19.46 mmol) was added dropwise by syringeand the RM was stirred for 1 h at −78° C. under N₂. The RM was quenchedwith sat. aq. NH₄Cl (20 mL) and allowed to warm to RT. The solvent wasremoved under reduced pressure and the residue was stored at −20° C. for18 h. H₂O (100 mL), brine (50 mL) and EtOAc (200 mL) were added. Theorganic layer was separated and washed with brine (100 mL) and driedover Na₂SO₄. The solvent was removed under reduced pressure to give abrown oil. The crude product was subjected to flash chromatography(silica, gradient heptane/EtOAc, 1:0 to 2:1). Impure [cis-rac]2-methyl-6-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridinewas dissolved in EtOAc (50 mL) and washed with aq. 1M K₂S₂O₃ (50 mL).The organic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The product was purified further using flash chromatography(silica, gradient heptane/EtOAc, 1:0 to 2:1) to give 0.76 g (47%) of[cis-rac]2-methyl-6-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridineas a colorless oil. Impure [trans-rac]2-methyl-6-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridineSC-303, obtained from the first CC, was also dissolved in EtOAc (50 mL)and washed with aq. 1M K₂S₂O₃ (50 mL) and brine (50 mL). The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure togive a colorless oil. This product was then lyophilised using MeCN/H₂O(3/1, v/v, 3 mL) to give 0.55 g (34%) of pure [trans-rac]2-methyl-6-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridineSC-303.

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]2-methyl-6-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine:δ=8.12 (s, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.72 (t,J=7.8 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.19 (d, J=7.7 Hz, 1H), 7.06 (d,J=7.7 Hz, 1H), 4.50 (dd, J=11.3, 2.1 Hz, 1H), 4.14 (m, 1H), 3.71 (td,J=12.2, 1.8 Hz, 1H), 2.51 (s, 3H), 2.28-1.99 (m, 1H), 1.84-1.75 (m, 1H),1.19 (t, J=7.5 Hz, 3H).

¹H-NMR (400 MHz, CDCl₃) of [trans-rac]2-methyl-6-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridineSC-303: δ=8.25 (s, 1H), 8.18 (d, J=7.9 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H),7.76 (t, J=7.8 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H),7.04 (d, J=7.6 Hz, 1H), 5.36 (dd, J=11.6, 2.4 Hz, 1H), 4.50 (td, J=12.2,2.7 Hz, 1H), 4.13 (dd, J=11.7, 4.7 Hz, 1H), 2.54 (s, 3H), 2.40-2.30 (m,1H), 2.27-2.17 (m, 1H), 2.12-1.98 (m, 1H), 1.88 (dd, J=15.5, 11.6 Hz,1H), 1.65 (dq, J=14.8, 7.4 Hz, 1H), 1.44 (dq, J=14.7, 7.4 Hz, 1H), 0.95(t, J=7.5 Hz, 3H).

The relative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyrimidine(Example 11)

Step 1:2-(2-(Trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

A solution of 2-(trifluoromethyl)pyrimidine-5-carbaldehyde (860 mg, 4.88mmol) and but-3-en-1-ol (0.420 mL, 4.88 mmol) in DCM (5.2 mL) was cooledto 0° C. MsOH (3.17 mL, 48.8 mmol) was added dropwise and the RM wasstirred at RT for 90 min. DCM (30 mL) was added, followed by the carefuladdition of sat. aq. NaHCO₃ (30 mL). The organic layer was washed withsat. aq. NaHCO₃ (2×30 mL), dried (Na₂SO₄) and evaporated under reducedpressure. The product was purified by flash chromatography (silica,gradient heptane/EtOAc, 1:0 to 1:1), to give 1.24 g (78%) of the desiredproduct.

Step 2:2-(Trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyrimidine

This reaction was performed in a three-necked flask under Ar. To asolution of2-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate(1.23 g, 3.77 mmol) in dry DMF (25 mL) was added K₂CO₃ (1.042 g, 7.54mmol). The RM was put under Ar/vacuum 5× in ca. 10 min,3-(trifluoromethyl)benzenethiol (2.56 mL, 18.85 mmol) was added and themixture was purged with Ar for 1 h. The RM was stirred at 50° C.overnight (hot-start). EtOAc (250 mL), brine (250 mL) and H₂O (250 mL)were added. The aq. layer was extracted with EtOAc (250 mL). Organiclayers were combined, washed with H₂O (250 mL) and brine (250 mL), dried(Na₂SO₄) and evaporated under reduced pressure. The product was purifiedby flash chromatography (silica, gradient heptane/EtOAc, 1:0 to 3:1), tofurnish 1.38 g (90%) of the desired product.

Step 3:2-(Trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyrimidine

To a solution of2-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyrimidine(1.33 g, 3.26 mmol) in MeOH (10 mL) was dropwise added oxone (2.89 g,min. 8.14 mmol) in H₂O (10 mL). The RM was stirred at RT overnight. MoreMeOH (10 mL) was added followed by the dropwise addition of oxone (2.89g, min. 8.14 mmol) in H₂O (10 mL). Stirring at RT was continuedovernight. The mixture was concentrated to evaporate most of the MeOH.EtOAc (100 mL) and H₂O (100 mL) were added. The organic layer was washedwith sat. aq. NaHCO₃ (100 mL), dried (Na₂SO₄) and evaporated underreduced pressure. The product was purified by flash chromategraphy(silica, gradient heptane/EtOAc, 1:0 to 1:1), to give 1.33 g (93%) ofthe desired product.

Step 4 was Carried Out in 3 Batches as Described Below: The ReactionVials were Dried (Heat-Gun) Before Use.

Step 4 (batch 1):5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyrimidine

A solution of2-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyrimidine(250 mg, 0.568 mmol) in dry THF (3.5 mL) was cooled to −78° C., 1 MKOt-Bu in THF (0.852 mL, 0.852 mmol) was added dropwise and 10 minlater, Mel (0.177 mL, 2.84 mmol) was added dropwise. The RM was stirredat −78° C. for 3.5 h. Half sat. aq. NH₄Cl (ca. 5 drops) was added andthe cooling bath was removed after 2 min. At RT, DCM (25 mL) and halfsat. aq. NH₄Cl (25 mL) were added. The aq. layer was extracted with DCM(2×25 mL). Organic layers were combined, dried (Na₂SO₄) and evaporatedunder reduced pressure.

Step 4 (batch 2):5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyrimidine

A solution of2-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyrimidine(250 mg, 0.568 mmol) in dry THF (3.5 mL) was cooled to −78° C., 1 MKOt-Bu in THF (0.852 mL, 0.852 mmol) was added dropwise and 10 minlater, Mel (0.177 mL, 2.84 mmol) was added dropwise. The RM was stirredat −78° C. for 3.5 h. Half sat. aq. NH₄Cl (ca. 5 drops) was added andthe cooling bath was removed after 2 min. At RT, DCM (25 mL) and halfsat. aq. NH₄Cl (25 mL) were added. The aq. layer was extracted with DCM(2×25 mL). Organic layers were combined, dried (Na₂SO₄) and evaporatedunder reduced pressure.

Step 4 (batch 3):5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyrimidine

A solution of2-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyrimidine(384 mg, 0.872 mmol) in dry THF (5 mL) was cooled to −78° C., 1 M KOt-Buin THF (1.308 mL, 1.308 mmol) was added dropwise and 10 min later, Mel(0.273 mL, 4.36 mmol) was added dropwise. The RM was stirred at −78° C.for 3.5 h. Half sat. aq. NH₄Cl (ca. 5 drops) was added and the coolingbath was removed after 2 min. At RT, DCM (50 mL) and half sat. aq. NH₄Cl(50 mL) were added. The aq. layer was extracted with DCM (2×50 mL).Organic layers were combined, dried (Na₂SO₄) and evaporated underreduced pressure.

The batches were combined and purified by flash chromatography (silica,gradient heptane/EtOAc, 1:0 to 2:1), to afford 380 mg (42%) of [cis-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyrimidine.

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyrimidine:δ=8.85 (s, 2H), 8.14 (s, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.98 (d, J=7.8 Hz,1H), 7.77 (t, J=7.8 Hz, 1H), 4.62 (dd, J=11.6, 1.8 Hz, 1H), 4.24 (dd,J=12.2, 4.3 Hz, 1H), 3.73 (td, J=12.4, 2.1 Hz, 1H), 2.41 (td, J=12.9,5.4 Hz, 1H), 2.18 (t, J=12.4 Hz, 1H), 1.86 (dt, J=13.0, 2.1 Hz, 1H),1.60 (s, 3H), 1.62-1.53 (m, 1.6H) [overlap with H₂O signal].

The relative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis racemic]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyrimidine

[Cis-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyrimidine(444 mg) was separated on a Jasco SFC (Chiralcel OJ-H, MeOH/EtOH 1:1;CO₂) to give 160 mg of [cis-EN1] SC-304 and 145 mg of [cis-EN2] SC-305.

[cis-EN1] SC-304—analytical chiral SFC: Jasco SFC, Chiralcel OJ, 5 um,250×4.6 mm, 40° C., 2 ml/Min CO₂/10% MeOH:EtOH (1:1), Ret. Time 4.52;ee>95%

[cis-EN2] SC-305—analytical chiral SFC: Jasco SFC, Chiralcel OJ, 5 um,250×4.6 mm, 40° C., 2 ml/Min CO₂/10% MeOH:EtOH (1:1), Ret. Time 5.19;ee>95%

2-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(Example 12)

Step 1: 2-(5-(Trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

A solution of 5-(trifluoromethyl)picolinaldehyde (3.82 g, 21.82 mmol) inDCM (20 mL) was prepared, followed by applying an ice/water bath anddropwise addition of methanesulfonic acid (14.1 mL, 218 mmol).Subsequently, 3-buten-1-ol (2.25 mL, 26.2 mmol) was added. The RM wasstirred at RT for 3 h and poured out in 10% aq. K₃PO₄ (300 mL). Additionof some ice and DCM (300 mL) resulted in a clear two phase system. Thephases were separated, the aq. layer was extracted with DCM (50 mL). Thecombination of organic layers was dried (brine & Na₂SO₄) andconcentrated in vacuo. The residue was dissolved in DCM (5 mL), additionof heptane (200 mL) was followed by evaporation of the DCM in vacuo.Trituration, followed by air-drying provided 5.25 g (59%, purity 80%) ofthe desired product as an off-white solid.

Step 2:5-(Trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

2-(5-(Trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (5.10 g, 12.5 mmol) was dissolved in dry MeCN (125 mL),the solution was degassed by N₂ purging for 30 min. K₂CO₃ (4.33 g, 31.4mmol) was added, followed by 3-(trifluoromethyl)benzenethiol (4.17 mL,31.4 mmol). The RM was stirred vigorously at 50° C. overnight.Subsequently, the RM was mixed with EtOAc (125 mL) and silica (5 g).Filtration over a cotton plug and washing of the residue with EtOAc(3×30 mL) was followed by concentration in vacuo. The residue of theconcentration was mixed with DCM (100 mL). Silica (20 g) was added, themixture was concentrated in vacuo. The residue was placed on top of asilica column and used for flash chromatography (silica, gradientheptane/EtOAc, 95:5 to 7:3) to result in 4.98 g (97%) of the desiredproduct as a clear oil.

Step 3:5-(Trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

5-(Trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(4.90 g, 12.0 mmol) was dissolved in MeOH (120 mL). A water bath wasapplied. Oxone (18.5 g, min. 52.0 mmol) was almost completely dissolvedin H₂O (70 mL), the turbid solution was added portionwise. The RM wasstirred vigorously at RT for 3 h. A turbid solution of oxone (4.55 g,min. 12.8 mmol) in H₂O (20 mL) was prepared and added to the RM,followed by MeOH (15 mL). The RM was stirred vigorously at RT for 1 h.The major part of the MeOH was removed from the RM by rotaryevaporation. The resulting suspension was mixed with H₂O (350 mL) andEtOAc (350 mL) to result in a clear two phase system. The layers wereseparated, the aq. layer was extracted with EtOAc (50 mL). Thecombination of organic layers was washed with sat. aq. NaHCO₃ (100 mL)and dried (brine and Na₂SO₄). Concentration in vacuo was followed bytrituration with heptane (100 mL). Filtration and air-drying wasfollowed by crystallisation from hot MeOH (25 mL) to provide 3.04 g(57%) of the desired product as a white solid.

Step 4:2-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine

A solution of5-(trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(2.00 g, 4.55 mmol) in dry THF (25 mL) was prepared, the temperature waslowered to −78° C. A solution of 1M LiHMDS in THF (6.83 mL, 6.83 mmol)was added dropwise and the RM was stirred at −78° C. for 10 min.Dropwise addition of Mel (0.569 mL, 9.10 mmol) was followed by stirringthe RM at −78° C. for 1 h. The RM was left in the cooling bath.Consequently, the temperature was kept at −78° C. for a few hours,followed by a slow raise of temperature to RT overnight. Subsequently,the RM was combined with aq. 1M KHSO₄ (150 mL), some ice and EtOAc (200mL) to result in a two phase system. The layers were separated, the aq.layer was extracted with EtOAc (50 mL). The combination of organiclayers was washed with sat. aq. NaHCO₃ (100 mL) and dried (brine andNa₂SO₄). Concentration in vacuo was followed by flash chromatography(silica, gradient heptane/EtOAc, 1:0 to 3:1) to give 1.55 g (75%) of[cis-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridineand 0.4 g (19%) of [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine:δ=8.80-8.72 (m, 1H), 8.12 (s, 1H), 8.05 (d, J=7.9 Hz, 1H), 8.00-7.92 (m,2H), 7.74 (t, J=7.8 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 4.60 (dd, J=9.5,4.5 Hz, 1H), 4.25 (ddd, J=11.9, 5.3, 1.2 Hz, 1H), 3.77 (td, J=12.4, 2.2Hz, 1H), 2.40 (td, J=12.9, 5.4 Hz, 1H), 2.13-2.00 (m, 2H), 1.66-1.60 (m,1H), 1.59 (s, 3H).

¹H-NMR (400 MHz, CDCl₃) of [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine:δ=8.82 (s, 1H), 8.23 (s, 1H), 8.17 (d, J=7.9 Hz, 1H), 8.01-7.91 (m, 2H),7.79 (t, J=7.8 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 5.42 (dd, J=11.4, 2.2Hz, 1H), 4.47 (td, J=12.2, 2.6 Hz, 1H), 4.11 (ddd, J=11.8, 5.6, 1.5 Hz,1H), 2.66 (dt, J=15.3, 2.2 Hz, 1H), 2.43 (dq, J=15.3, 2.0 Hz, 1H), 1.87(ddd, J=15.4, 12.5, 5.7 Hz, 1H), 1.70 (dd, J=15.4, 11.5 Hz, 1H), 1.23(s, 3H).

The relative stereochemistry was assigned by 2D-NMR. For [cis-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridinea NOE was observed for the Me-group with H4_(ax). For [trans-rac]2-[4-methyl-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridinea NOE was observed for the sulfone aromate with H⁴ _(ax).

Chiral resolution of [cis-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine

[Cis-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(600 mg, 1.323 mmol) was subjected to preparative chiral-LC (IC-column,heptane/i-PrOH, 9:1). The products were dried to give 225 mg (38%) of

[cis-EN1] SC-308 and 215 mg (36%) of [cis-EN2] SC-309.

[cis-EN1] SC-308—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/iPrOH 95/5, Ret. Time 14.847; ee>95%/specificrotation [α]_(D) ^(27.6) −35.5° (c 0.96; MeOH).

[cis-EN2] SC-309—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/iPrOH 95/5, Ret. Time 26.630; ee>95%/specificrotation [α]_(D) ^(27.7) +34.8° (c 0.91; MeOH).

Chiral resolution of [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine

[Trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(0.4 g, 0.882 mmol) was subjected to preparative chiral-LC (IC-column,heptane/i-PrOH, 9:1) to afford 142 mg (36%) of [trans-EN1] SC-310 and144 mg (36%) of [trans-EN2] SC-311.

[trans-EN1] SC-310—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ),1 ml/min, 35° C., heptane/iPrOH 95/5, Ret. Time 8.776; ee>95%

[trans-EN2] SC-311—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ),1 ml/min, 35° C., heptane/iPrOH 95/5, Ret. Time 13.639; ee>95%

3-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-methyl-pyridine(Example 13)

The synthesis was carried out in analogy to2-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-methyl-pyridine(see above). The crude product obtained in the last step was subjectedto flash chromatography (silica, gradient heptane/EtOAc, 84:16 to 0:1)to yield [cis-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-methyl-pyridine(172 mg, 17%).

[Trans-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-methyl-pyridineSC-314 (126 mg, 12%) was also obtained.

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-methyl-pyridine:δ=8.44 (d, J=4.8 Hz, 1H), 8.12 (s, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.96 (d,J=7.7 Hz, 1H), 7.78-7.68 (m, 2H), 7.18 (dd, J=7.8, 4.8 Hz, 1H), 4.61 (m,1H), 4.15 (dd, J=12.0, 5.2 Hz, 1H), 3.71 (t, J=12.3 Hz, 1H), 2.52 (s,3H), 2.28 (td, J=12.8, 5.2 Hz, 1H), 2.18-1.95 (m, 5H), 1.71 (d, J=13.1Hz, 1H), 1.19 (t, J=7.5 Hz, 3H).

¹H-NMR (400 MHz, CDCl₃) of [trans-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-methyl-pyridineSC-314: δ=8.44 (dd, J=4.8, 1.7 Hz, 1H), 8.18 (s, 1H), 8.11 (d, J=7.9 Hz,1H), 7.96 (d, J=7.8 Hz, 1H), 7.82-7.72 (m, 2H), 7.17 (dd, J=7.8, 4.8 Hz,1H), 5.50 (dd, J=11.6, 2.1 Hz, 1H), 4.49 (td, J=12.2, 2.8 Hz, 1H), 4.12(dd, J=11.8, 4.7 Hz, 1H), 2.69 (s, 3H), 2.34 (d, J=15.4 Hz, 1H),2.17-1.93 (m, 2H), 1.67-1.41 (m, 3H), 0.94 (t, J=7.4 Hz, 3H).

The relative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-methyl-pyridine

[Cis-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-methyl-pyridine(172 mg, 0.416 mmol) was subjected to preparative chiral-LC (IC-column,heptane/EtOH, 90:10) to give [cis-EN1] SC-312 (67 mg, 39%) and [cis-EN2]SC-313 (63 mg, 37%).

[cis-EN1] SC-312—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 80/20, Ret. Time 16.332; ee>95%

[cis-EN2] SC-313—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 80/20, Ret. Time 21.846; ee>95%

5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyridine(Example 14)

Step 1: 2-(6-(Trifluoromethyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

Methanesulfonic acid (13.0 mL, 200 mmol) was dropwise added to asolution of 6-(trifluoromethyl)nicotinaldehyde (3.50 g, 20.0 mmol) andbut-3-en-1-ol (1.72 mL, 20.0 mmol) in DCM (20 mL) while cooling with anicebath. The RM was stirred at RT for 4 h, diluted with DCM, washed withsat. aq. NaHCO₃ and separated with a phase separator. The organic layerwas further diluted with DCM, washed with sat. aq. NaHCO₃ (2×), dried(Na₂SO₄) and concentrated. Crystallisation (EtOAc/heptane) of theresidue gave the product (3.48 g, 54%) as white crystals. The motherliquor was concentrated and crystallisation (EtOAc/Heptane/i-Pr₂O) ofthe residue gave another crop of product (1.73 g, 27%) as whitecrystals. The crystals were combined to give the desired product (5.21g, 80%).

Step 2:2-(Trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

2-(6-(Trifluoromethyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (4.19 g, 12.9 mmol) was dissolved in dry DMF (40 mL),the solution was degassed by N₂ bubbling for 1 h. K₂CO₃ (4.45 g, 32.2mmol) was added, followed by 3-(trifluoromethyl)benzenethiol (3.43 mL,25.8 mmol). The RM was stirred vigorously at 50° C. overnight and pouredout into ice-water (400 mL), followed by addition of EtOAc (200 mL). Thelayers were separated, the aq. layer was extracted with EtOAc (50 mL).The combination of organic layers was washed with H₂O (50 mL), dried(brine and Na₂SO₄) and concentrated in vacuo. The residue was mixed withDCM (3 mL) and used for flash chromatography (silica, gradientheptane/EtOAc, 95:5 to 7:3) to result in the desired product (5.19 g,99%) as a clear oil.

Step 3:2-(Trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

2-(Trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(5.19 g, 12.7 mmol) was dissolved in MeOH (120 mL). A water bath wasapplied. Oxone (19.6 g, min. 55.1 mmol) was almost completely dissolvedin H₂O (70 mL), the turbid solution was added portionwise. During theaddition, a raise of temperature was observed, the temperature was keptbelow 25° C. The RM was stirred vigorously at RT for 4 h. The major partof the MeOH was removed in vacuo. The resulting suspension was mixedwith H₂O (350 mL) and EtOAc (350 mL) to result in a clear two phasesystem. The layers were separated, the aq. layer was extracted withEtOAc (50 mL). The combination of organic layers was washed with sat.aq. NaHCO₃ (50 mL), dried (brine and Na₂SO₄) and concentrated in vacuo.Trituration with heptane (100 mL) and air-drying provided the desiredproduct (4.99 g, 89%) as a white solid.

Step 4 was Carried Out in 2 Batches as Described Below:

Step 4 (batch 1):5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyridine

While cooling with an acetone/dry ice bath under Ar, KOt-Bu (230 mg,2.05 mmol) was portionwise added to a solution of2-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(600 mg, 1.37 mmol) in dry THF (4 mL). After the RM was stirred for 5min while still cooling with an acetone/dry ice bath, Mel (0.171 mL,2.73 mmol) was added to the RM. The RM was stirred for 30 min whilestill cooling with an acetone/dry ice bath. The RM was allowed to warmto RT, diluted with DCM, washed with H₂O and brine and concentrated. Theresidue was subjected to flash chromatography (silica, gradientheptane/EtOAc, 95:5→1:1). Crystallisation (EtOAc/heptane) of the residuegave impure product. The crystals and the mother liquor were combinedand concentrated. The residue was purified by flash chromatography(silica, gradient heptane/EtOAc, 94:6→34:66) and flash chromatography(silica, gradient heptane/EtOAc, 95:5 to 1:1) resulting in [cis-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyridineSC-306 (95 mg, 15%). Impure product, which was also obtained, was thenfurther purified by flash chromatography (silica, gradientheptane/EtOAc, 95:5-1:1) and co-evaporated with MeOH and pentane toyield [trans-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyridineSC-307 (173 mg, 28%).

Step 4 (batch 2):5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyridine

A solution of2-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(1.00 g, 2.28 mmol) in dry THF (15 mL) was prepared, the temperature waslowered to −78° C. A solution of 1 M KOt-Bu in THF (3.41 mL, 3.41 mmol)was added dropwise and the RM was stirred at −78° C. for 10 min.Dropwise addition of Mel (0.285 mL, 4.55 mmol) was followed by stirringthe RM at −78° C. for 1 h. The flask was left in the cooling bath.Consequently, the temperature was kept at −78° C. for a few hours,followed by slow raise of temperature to RT and stirring overnight atRT. The RM was combined with aq. 1 M KHSO₄ (75 mL), some ice and EtOAc(100 mL) to result in a two phase system. The layers were separated, theaq. layer was extracted with EtOAc (25 mL). The combination of organiclayers was washed with sat. aq. NaHCO₃ (50 mL), dried (brine and Na₂SO₄)and concentrated in vacuo. The residue was dissolved in DCM (5 mL) andused for flash chromatography (silica, gradient heptane/EtOAc,95:5-6:4). The product was dissolved in EtOAc (200 mL), the solution waswashed with aq. 1 M Na₂S₂O₃ (50 mL), dried (brine and Na₂SO₄) andconcentrated in vacuo. The residue was dissolved in DCM (3 mL), followedby addition of heptane (15 mL) and concentration in vacuo. The residuewas triturated in pentane (20 mL). Filtration and drying provided 566 mg(54%) of [cis-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyridineSC-306 as a white solid.

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyridineSC-306: δ=8.62 (d, J=1.6 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J=7.9 Hz, 1H),7.97 (d, J=7.8 Hz, 1H), 7.88 (dd, J=8.1, 1.7 Hz, 1H), 7.75 (t, J=7.8 Hz,1H), 7.70 (d, J=8.1 Hz, 1H), 4.58 (dd, J=11.6, 1.8 Hz, 1H), 4.26-4.17(m, 1H), 3.73 (td, J=12.4, 2.2 Hz, 1H), 2.39 (td, J=12.9, 5.4 Hz, 1H),2.16 (t, J=12.3 Hz, 1H), 1.80 (dt, J=13.0, 2.2 Hz, 1H), 1.61-1.58 (m,1H), 1.59 (s, 3H).

¹H-NMR (400 MHz, CDCl₃) of [trans-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyridineSC-307: δ=8.74 (s, 1H), 8.17 (s, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.99 (d,J=7.8 Hz, 1H), 7.89 (d, J=6.8 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.69 (d,J=8.1 Hz, 1H), 5.38 (d, J=9.9 Hz, 1H), 4.45 (td, J=12.5, 2.4 Hz, 1H),4.10 (dd, J=11.9, 4.9 Hz, 1H), 2.54 (d, J=15.3 Hz, 1H), 2.27 (d, J=15.4Hz, 1H), 1.86 (ddd, J=15.5, 12.8, 5.7 Hz, 1H), 1.65-1.52 (m, 1H), 1.25(s, 3H).

The relative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis racemic]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-Pyran-2-yl]-2-(trifluoromethyl)-pyridineSC-306

[Cis-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyridineSC-306 (556 mg) was separated on a Jasco SFC (Chiralcel OJ-H, MeOH/EtOH1:1; CO₂) to give 220 mg of [cis-EN1] SC-315 and 214 mg of [cis-EN2]SC-316.

[cis-EN1] SC-315—analytical chiral SFC: Jasco SFC, Chiralcel OJ, 5 um,250×4.6 mm, 40° C., 2 ml/Min CO₂/10% MeOH:EtOH 1:1, Ret. Time 3.56;ee>95%

[cis-EN2] SC-316—analytical chiral SFC: Jasco SFC, Chiralcel OJ, 5 um,250×4.6 mm, 40° C., 2 ml/Min CO₂/10% MeOH:EtOH 1:1, Ret. Time 4.34;ee>95%

3-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2,6-dimethyl-pyridine(Example 15)

Step 1:2-(2,6-Dimethylpyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

A solution of 2,6-dimethylnicotinaldehyde (4.87 g, 36.0 mmol) andbut-3-en-1-ol (3.10 mL, 36.0 mmol) in DCM (35 mL) was cooled in aNaCl/ice bath to −16° C. MsOH (23.4 mL, 360 mmol) was added slowly via asyringe over 20 min, keeping the temperature below −10° C. The RM waspoured out in a cooled solution of Na₂CO₃ (38.2 g, 360 mmol) in H₂O(˜300 mL) and the product was extracted with EtOAc (2×200 mL). Thecombined organic layers were washed with sat. aq. NaHCO₃ (2×50 mL) andbrine (2×50 mL) before drying on Na₂SO₄ and concentration in vacuo. Theproduct was purified using flash chromategraphy (silica, gradientheptane/acetone, 7:3 to 4:6) to give the desired product (5.86 g, 57%)as a brown oil.

Step 2:2,6-Dimethyl-3-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

A solution of2-(2,6-dimethylpyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (3g, 10.51 mmol) in dry DMF (60 mL) was degassed by applying vacuum for 1min, then refill the flask with Ar. This sequence was repeated 5 timesbefore Cs₂CO₃ (8.56 g, 26.3 mmol) and 3-(trifluoromethyl)benzenethiol(3.49 mL, 26.3 mmol) were added. The degassing sequence was performedtwo times and the mixture was subsequently stirred at 80° C. under argonfor 2 h. The heating was stopped and the stirring was continued at RTfor 16 h. The RM was poured out in sat. aq. NaHCO₃ (50 mL) and theproduct was extracted with EtOAc/i-Pr₂O (1/1, v/v, 2×100 mL). Thecombined organic layers were washed with sat. aq. NaHCO₃ (2×50 mL) andbrine (2×50 mL) before drying on Na₂SO₄ and concentration in vacuo. Theproduct was purified using flash chromatography (silica, gradientheptane/EtOAc, 1:0 to 4:6) to give the desired product (2.89 g, 74%) asa light yellow oil.

Step 3:2,6-Dimethyl-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a solution of2,6-dimethyl-3-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(2.89 g, 7.87 mmol) in MeOH (115 mL) was added a solution of oxone (4.84g, min. 13.6 mmol) in H₂O (80 mL) and the suspension was stirred at RTfor 30 min. The MeOH was distilled off in vacuo. The residue wasbasified with sat. aq. NaHCO₃ and the product was extracted withi-Pr₂O/EtOAc (1/1, v/v, 250 mL). The organic layer was washed with sat.aq. NaHCO₃ (2×50 mL) and brine (2×50 mL) before drying on Na₂SO₄ andconcentration in vacuo to give the desired product (2.95 g, 94%) as awhite solid.

Step 4:3-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2,6-dimethyl-pyridine

To a solution of2,6-dimethyl-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(2 g, 5.01 mmol) in dry THF (15 mL) under argon at −78° C. was added 1MKO-tBu in THF (15.02 mL, 15.02 mmol) dropwise over 10 min. The mixturewas stirred for 30 min. Ethyl iodide (2.0 mL, 25.04 mmol) was addeddropwise, and the stirring was continued at −78° C. for 4 h. More 1MKOt-Bu in THF (15.02 mL, 15.02 mmol) was added slowly via a syringe andthe mixture was stirred at −78° C. for 30 min. Ethyl iodide (1.6 mL,20.03 mmol) was added dropwise over 1 min and the stirring wascontinued, slowly warming up to RT for 72 h. The RM was diluted withsat. aq. NaHCO₃ (50 mL) and the product was extracted with EtOAc/i-Pr₂O(1/1, v/v, 2×100 mL). The combined organic layers were washed with sat.aq. NaHCO₃ (2×50 mL), aq. 1M Na₂S₂O₃ (2×50 mL) and brine (2×50 mL)before drying on Na₂SO₄ and concentration in vacuo. The product waspurified using flash chromatography (silica, gradient heptane/EtOAc,9:1→3:7) to give impure [trans-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2,6-dimethyl-pyridineSC-319 and 905 mg (42%) of [cis-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2,6-dimethyl-pyridine.Impure [trans-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2,6-dimethyl-pyridineSC-319 was purified further using flash chromatography (silica, gradientheptane/EtOAc, 9:1 3:7) to give (383 mg, 17%) of pure [trans-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2,6-dimethyl-pyridineSC-319 as a white solid.

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2,6-dimethyl-pyridine:δ=8.12 (s, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.74 (t,J=7.9 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 4.58 (dd,J=9.6, 3.6 Hz, 1H), 4.14 (dd, J=11.8, 4.7 Hz, 1H), 3.71 (td, J=12.3, 1.8Hz, 1H), 2.50 (d, J=13.6 Hz, 6H), 2.26 (td, J=12.9, 5.3 Hz, 1H),2.17-1.91 (m, 4H), 1.71 (d, J=13.3 Hz, 1H), 1.18 (t, J=7.5 Hz, 3H).

¹H-NMR (400 MHz, CDCl₃) of [trans-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2,6-dimethyl-pyridineSC-319: δ=8.18 (s, 1H), 8.10 (d, J=7.9 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H),7.76 (t, J=7.8 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H),5.47 (dd, J=11.6, 2.0 Hz, 1H), 4.48 (td, J=12.2, 2.7 Hz, 1H), 4.10 (dd,J=11.7, 5.1 Hz, 1H), 2.65 (s, 3H), 2.52 (s, 3H), 2.29 (d, J=15.4 Hz,1H), 2.16-2.06 (m, 1H), 2.06-1.93 (m, 1H), 1.60 (dd, J=15.4, 11.6 Hz,1H), 1.54-1.44 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).

The relative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2,6-dimethyl-pyridine

[Cis-rac]3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2,6-dimethyl-pyridine(300 mg, 0.702 mmol) was subjected to preparative chiral-LC (IC-column,heptane/EtOH, 9:1) to give 131 mg (43%) of [cis-EN1] SC-317 and 126 mg(42%) of [cis-EN2] SC-318.

[cis-EN1] SC-317—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 80/20, Ret. Time 13.219; ee>95%

[cis-EN2] SC-318—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 80/20, Ret. Time 16.495; ee>95%

2-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-methyl-pyridine(Example 16)

Chiral resolution of [cis rac]2-methyl-6-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

[Cis rac]2-methyl-6-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(350 mg, 0.847 mmol) was subjected to preparative chiral-LC (OD-column,heptane/EtOH, 95:5) and the products were lyophilised using MeCN/H₂O(3/1, v/v, 2 mL) to give 130 mg (37%) of [cis-EN1] SC-323 and 127 mg(36%) of [cis-EN2] SC-324.

[cis-EN1] SC-323—analytical chiral HPLC: chiralpak OD-H (250×4.6 mm 5μ),1 ml/min, 35° C., heptane/EtOH 90/10, Ret. Time 6.670; ee>95%

[cis-EN2] SC-324—analytical chiral HPLC: chiralpak OD-H (250×4.6 mm 5μ),1 ml/min, 35° C., heptane/EtOH 90/10, Ret. Time 9.340; ee>95%

3-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 17)

Two enantiomers of cis racemic were separated by SFC using on a chiralpack OJ-H column to obtain two desired cis enantiomers (SC-325 andSC-326).

SC-325: 1^(st) eluted enantiomer: [cis-EN1] SC-325

SC-326: 2^(nd) eluted enantiomer: [cis-EN2] SC-326

2-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine(Example 18)

Step 1: 2-(5-Cyclopropylpyrazin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

A solution of 5-cyclopropylpyrazine-2-carbaldehyde (4.80 g, 32.4 mmol)in DCM(30 mL) was prepared, followed by applying an ice/water bath anddropwise addition of MsOH (21.04 mL, 324 mmol). Subsequently,3-buten-1-ol (3.35 mL, 38.9 mmol) was added dropwise. The RM was stirredat 0° C. for 1.5 h. Sat. aq. Na₂CO₃ (400 mL) was immersed in anice/water bath. The RM was transferred into a separation funnel andadded dropwise to the stirred and chilled Na₂CO₃ solution. Thetemperature was kept below 15° C. Subsequently, DCM (125 mL) and H₂O(100 mL) were added, followed by separation of the phases. The aq. layerwas extracted with DCM (2×50 mL). The combination of organic layers waswashed with sat. aq. NaHCO₃ (50 mL), dried (brine twice & Na₂SO₄) andconcentrated to yield 9.59 g (99%) of the desired product as a brownoil.

Step 2:2-Cyclopropyl-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyrazine

A solution of 2-(5-cyclopropylpyrazin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (9.59 g, 32.1 mmol) in dry MeCN (300 mL) was degassedby N₂ bubbling for 1 h. K₂CO₃ (7.55 g, 54.6 mmol) was added, followed by3-(trifluoromethyl)benzenethiol (7.27 mL, 54.6 mmol). The RM was stirredat 50° C. overnight. Addition of EtOAc (100 mL) and silica (10 g) wasfollowed by filtration over a cotton plug. The residue was washed withEtOAc (2×100 mL), the combination of filtrates was concentrated. Theresidue was mixed with DCM (100 mL). Silica (40 g) was added, themixture was concentrated. The residue was placed on top of a silicacolumn and used for flash chromatography (silica, gradientheptane/EtOAc, 100:0 to 7:3) to result in 7.62 g (62%) of the desiredproduct as a colourless oil.

Step 3:2-Cyclopropyl-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyrazine

2-Cyclopropyl-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyrazine(7.60 g, 19.98 mmol) was dissolved in MeOH (200 mL). An ice/water bathwas applied. Oxone (30.7 g, min. 86.3 mmol) was almost completelydissolved in H₂O (100 mL) and the turbid solution was added portionwise.During the addition, a raise of temperature was observed, thetemperature was kept below 15° C. The reaction mixture was stirredvigorously at RT for 2 h. The major part of the MeOH was removed fromthe RM by rotary evaporation. The resulting suspension was mixed withH₂O (500 mL) and EtOAc (500 mL) to result in a two phase system with awhite solid. The layers were decanted and separated. The aq. layer wascombined with the white solid and mixed with EtOAc (100 mL). The layerswere decanted and separated. The combination of organic layers waswashed with sat. aq. NaHCO₃ (100 mL), dried (brine and Na₂SO₄) andconcentrated. The residue was dissolved in DCM (100 mL) andconcentrated. The residue was dissolved in DCM (10 mL), followed byaddition of MeOH (100 mL) and concentration. The residue was dissolvedin MeOH (20 mL) by heating. Cooling to RT started crystallisation.Filtration, washing with MeOH (3×10 mL) and drying by suction provided5.72 g (69%) of the desired product as a white powder.

Step 4:2-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine

A solution of2-cyclopropyl-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyrazine(1.50 g, 3.64 mmol) in dry THF (20 mL) was prepared. The temperature waslowered to −78° C., 1 M KOt-Bu in THF (5.46 mL, 5.46 mmol) was addeddropwise and the RM was stirred for 10 min. Dropwise addition of Mel(0.455 mL, 7.27 mmol) was followed by stirring the RM at −78° C. for afew hours, followed by slow raise of temperature to RT and stirringovernight at rt. The RM was combined with aq. 1 M KHSO₄ (100 mL) andEtOAc (120 mL) to result in a two phase system. The layers wereseparated, the aq. layer was extracted with EtOAc (25 mL). Thecombination of organic layers was washed with aq. 1 M Na₂S₂O₃ (30 mL),sat. aq. NaHCO₃ (50 mL) and dried (brine and Na₂SO₄), followed byconcentration. The residue was dissolved in DCM (3 mL) and used forflash chromatography (silica, gradient heptane/EtOAc, 9:1 to 65:35).This resulted in two fractions, the first fraction was used for furtherpurification in this experiment. The second fraction was collected toarrive at 0.90 g (58%) of [cis rac]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazineas a white solid. The first fraction mentioned above was dissolved inDCM (0.7 mL) and used for flash chromatography (silica, gradientheptane/EtOAc, 95:5 to 4:1). The product was dissolved in MeCN (10 mL),followed by concentration. The residue was dissolved in MeCN (2 mL),followed by addition of H₂O (2 mL) and freeze drying to result in 117 mg(7%) of [trans rac]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazineSC-328.

¹H NMR (400 MHz, CDCl₃) of [cis racemic]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine:δ 8.52-8.46 (m, 1H), 8.36 (d, J=1.3 Hz, 1H), 8.13 (s, 1H), 8.05 (d,J=7.9 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 4.54 (dd,J=11.6, 2.2 Hz, 1H), 4.22 (dd, J=11.5, 4.7 Hz, 1H), 3.74 (td, J=12.3,2.1 Hz, 1H), 2.37 (td, J=12.8, 5.4 Hz, 1H), 2.17 (t, J=12.3 Hz, 1H),2.06 (p, J=6.5 Hz, 1H), 1.94 (dt, J=12.9, 2.2 Hz, 1H), 1.65-1.55 (m,9.6H) [+H₂O], 1.07 (d, J=6.7 Hz, 4H).

¹H-NMR (400 MHz, CDCl₃) of [trans rac]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazineSC-328: δ 8.51 (s, 1H), 8.41 (d, J=1.3 Hz, 1H), 8.19 (s, 1H), 8.13 (d,J=7.7 Hz, 1H), 7.96 (d, J=7.7 Hz, 1H), 7.77 (t, J=7.8 Hz, 1H), 5.35 (dd,J=11.4, 2.5 Hz, 1H), 4.44 (td, J=12.2, 2.5 Hz, 1H), 4.13-4.03 (m, 1H),2.52 (d, J=15.4 Hz, 1H), 2.36 (d, J=15.3 Hz, 1H), 2.14-2.03 (m, 1H),1.98-1.82 (m, 2H), 1.24 (s, 3H), 1.06 (d, J=7.0 Hz, 4H).

The relative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis rac] and [trans rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis racemic]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine

[Cis rac]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine(300 mg, 0.703 mmol) was subjected to preparative chiral-LC (IC-column,heptane/EtOH 9:1). The two products were dissolved in EtOAc (20 mL),followed by concentration. The residues were dissolved in DCM (5 mL),added to heptane (30 mL) followed by concentration. The residues weresuspended in heptane (10 mL), filtration and drying by suction provided114 mg (38%) of [cis-EN1] SC-327 and 101 mg (34%) of [cis-EN2] SC-329.

[cis-EN1] SC-327—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 80/20, Ret. Time 8.057; ee>95%

[cis-EN2] SC-329—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 80/20, Ret. Time 11.174; ee>95%

5-Cyclopropyl-3-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole(Example 19)

Step 1: 4-Oxo-tetrahydro-pyran-2-carboxylic acid

To a degassed solution of 4-oxo-4H-pyran-2-carboxylic acid (7 g, 50.0mmol, 1 eq) in EtOAc (130 mL) was added palladium/carbon (0.700 g, 10%by weight) and the mixture was again degassed thoroughly with Ar andstirred in a paar shaker for 16 h under H₂. Reaction was monitored byTLC. The RM was filtered through celite bed and organic portion wasconcentrated under reduced pressure to crude4-oxotetrahydro-2H-pyran-2-carboxylic acid (3.8 g, 53%) as white solidwhich was used for next step without further purification.

Step 2: 2-(hydroxymethyl)tetrahydro-2H-pyran-4-ol

To a stirred solution of 4-oxotetrahydro-2H-pyran-2-carboxylic acid (3g, 20.54 mmol, 1 eq) in THF (100 mL) borane dimethyl sulfoxide (18.24 g,240 mmol, 12 eq) was slowly added at 0° C. and the mixture was stirredunder reflux for 6 h. Reaction was monitored by TLC. The RM was slowlyquenched with water at 0° C. and filtered through celite bed and organiclayer was concentrated under reduced pressure to obtain crude product asa solid. Further this solid was washed with 30% i-PrOH/CHCl₃. Theorganic solvents were evaporated under reduced pressure to get crude2-(hydroxymethyl)tetrahydro-2H-pyran-4-ol (2 g, 74%) as light brownliquid.

Step 3: 2-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-4-ol

To a solution of 2-(hydroxymethyl)tetrahydro-2H-pyran-4-ol (7.0 g, 53mmol, 1 eq) in DCM (130 ml) was added TEA (8.8 mL, 63.6 mmol, 1.2 eq)and DMAP (0.258 g, 2.1 mmol, 0.04 eq) followed by tertiary butyl silylchloride (6.3 g, 42.4 mmol, 0.8 eq) at 0° C. Then the RM was stirred atRT for 12 h. The RM was diluted with DCM (200 mL) and washed with water(3×100 mL), brine, dried over anhydr. Na₂SO₄, filtered and concentratedunder reduced pressure to give the crude product. The crude product waspurified by CC o afford pure2-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-4-ol (3.5 g,27%) as light yellow liquid.

Step 4: 2-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-4-ylmethanesulfonate

To a solution of2-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-4-ol (2.6 g,10.5 mmol, 1 eq) in DCM (50 mL) was added TEA (4.3 mL, 30 mmol, 3 eq)followed by methane sulfonyl chloride (1.55 mL, 20 mmol, 1 eq) at 0° C.Then the RM was stirred at the same temperature for 1 h. The RM wasdiluted with DCM (100 mL) and washed with water (3×50 mL), brine, driedover anhydr. Na₂SO₄, filtered and concentrated under reduced pressure togive the crude2-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-4-ylmethanesulfonate (2.8 g, 82%) as a yellow liquid which was used for thenext step without further purification.

Step 5:tert-butyldimethyl((4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)methoxy)silane

To a stirred solution of2-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-4-ylmethanesulfonate (3.5 g, 10.8 mmol, 1 eq) in DMF (100 mL)3-(trifluoromethyl)benzenethiol (2.8 g, 15.7 mmol, 1.5 eq), K₂CO₃ (2.76g, 20 mmol, 2 eq) was added and the mixture was heated to 70° C. for 12h. The reaction was monitored by TLC. The RM was diluted with EtOAc (50mL), washed with water (2×20 mL) and sat. brine, dried over anhydr.Na₂SO₄ and filtered. The organic solvent was evaporated under reducedpressure to get crude product which was purified by flash chromatographynt to afford puretert-butyldimethyl((4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)methoxy)silane(2 g, 47%) as a light yellow liquid.

Step 6:tert-butyldimethyl((4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methoxy)silane

To a stirred solution oftert-butyldimethyl((4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)methoxy)silane(2.2 g, 5.41 mmol, 1 eq) in (3:1) mixture of MeCN (72 mL) and water (24mL), sodium periodate (3.47 g, 16.1 mmol, 2 eq) was added followed byaddition of ruthenium(III)chloride hydrate (0.022 g, 0.106 mmol, 0.02eq) at 0° C. The RM was stirred for 10 min at RT. The reaction wasmonitored by TLC and it was diluted with EtOAc (100 mL), washed withwater (2×50 mL), and brine (50 ml). The organic layer was dried overNa₂SO₄, filtered and concentrated in reduced pressure to get crudeproduct which was purified by CC to afford puretert-butyldimethyl((4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methoxy)silane(1.7 g, 74%) as off white solid.

Step 7:tert-butyldimethyl((4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methoxy)silane

To a stirred solution oftert-butyldimethyl((4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methoxy)silane(2.5 g, 5.70 mmol, 1 eq) in THF (80 mL), NaHMDS (11.4 mL, 11.4 mmol, 2eq) was added followed by addition of 15-crown-5 (2.5 g, 11.36 mmol, 2eq) at −78° C. The reaction was continued for 20 min. Mel was added andthe RM was maintained for 45 min at −78° C. and then allowed to warm upto RT and stirred for further 12 h. The reaction was monitored by TLCand it was diluted with EtOAc (100 mL), washed with water (2×50 mL),brine (50 mL), dried over anhydr. Na₂SO₄, filtered and evaporated underreduced pressure to give crude product which was further purified by CCto afford puretert-butyldimethyl((4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methoxy)silane(1.3 g, 52%) as light yellow solid.

Step 8:(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methanol

To a cooled (0° C.) stirred solution oftert-butyldimethyl((4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methoxy)silane(0.83 g, 1.8 mmol, 1 eq) in THF (20 mL) TBAF solution (4.5 mL, 4.5 mmol,2.5 eq) was added. The RM was stirred for 30 min at RT. Reaction wasmonitored by TLC, solvent was evaporated under reduced pressure to getcrude product which was purified by CC to afford pure(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-methanol(0.58 g, 94%) as a white solid.

Step 9:4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxylicacid

To a cooled (0° C.) solution of CrO₃ (7.39 g, 73.96 mmol, 5.0 eq) in H₂O(14.2 mL) was added H₂SO₄ (7.7 mL) dropwise under vigorous stirring.This freshly prepared solution (Jones reagent) was slowly added to(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methanolin acetone at 0° C. and then the RM was stirred for 1 h at RT. The RMwas poured into ice water, diluted with EtOAc (400 mL) washed with water(2×100 mL), brine (100 mL) and the organic part was dried over Na₂SO₄,concentrated to get pure4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxylicacid (4.0 g, 77%) as off white solid.

Step 10&11:4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide

To a solution of4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxylicacid (4.0 g, 11.36 mmol) in dry THF (102 mL) and TEA (4.74 mL, 34.09mmol, 3.0 eq) was added ethyl chloroformate (2.16 mL, 22.72 mmol, 2.0eq.) in THF (51 mL) at −10° C. The RM was allowed to stir at 0° C. for 1h and then at RT for another 1 h. Then ammonia gas was purged into RMfor 30 min. RM was diluted with DCM (100 mL) and solid residue wasfiltered off. Organic layer was washed with water (50 mL), sat. NaHCO₃solution (50 mL), brine (50 mL) dried over Na₂SO₄ and concentrated underreduced pressure to give the crude product. The crude product wastriturated with hexane to give the sufficiently pure desired4-methyl-4-((3-(trifluoromethyl)phenyl)-sulfonyl)tetrahydro-2H-pyran-2-carboxamide(3.0 g, 75%) as off white solid.

Step 12:4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbonitrile

To a solution of4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide(1.5 g, 4.27 mmol) in dry DMF (5.3 mL) was added cyanuric chloride(0.788 g, 4.27 mmol, 1.0 eq) at 0° C. and then the RM was stirred at RTfor 2 h. The RM was diluted with water (100 mL) and extracted with EtOAc(2×150 mL). Organic layer was separated, washed with water (50 mL),brine (50 mL) dried over Na₂SO₄ and concentrated under reduced pressureand the residue was purified by CC to afford4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbonitrile(0.6 g, 42%) as off white solid.

Step 13:(Z)—N′-hydroxy-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboximidamide

To a well-stirred solution of hydroxylamine hydrochloride (0.375 g, 5.4mmol, 1.5 eq.) and TEA (1.0 ml, 7.2 mmol, 2 eq.) in 1,4-dioxane (10 ml)was added a solution of4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbonitrile(1.2 g, 3.6 mmol) in dioxane (10 mL) at RT and then the RM was heated toreflux for 3 h. The RM was concentrated under reduced pressure and theresidue was purified by CC to afford(Z)—N′-hydroxy-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboximidamide(1.0 g, 76%) as off white solid.

Step 14:(Z)—N′-((cyclopropanecarbonyl)oxy)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboximidamide

To a stirring solution of(Z)—N′-hydroxy-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboximidamide(0.6 g, 1.63 mmol) in dichloromethane (10 mL) under N₂ at 0° C. wasadded TEA (0.68 mL, 4.91 mmol, 3.0 eq). Then cyclopropylcarbonylchloride(0.134 mL, 1.47 mmol, 0.9 eq [dissolved in 10 mL of DCM]) was added dropwise at 0° C. and the resulting RM was stirred for 2 h at 0° C. The RMwas diluted with water (50 mL), extracted with DCM (2×50 mL) combinedorganic part was washed with brine (50 mL), dried over Na₂SO₄,concentrated under reduced pressure and the residue was purified by CCto afford(Z)—N′-((cyclopropanecarbonyl)oxy)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-tetrahydro-2H-pyran-2-carboximidamide(0.6 g, 84%) as off white solid.

Step 15:5-cyclopropyl-3-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1,2,4-oxadiazole

A solution of(Z)—N′-((cyclopropanecarbonyl)oxy)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboximidamide(1.0 g, 2.3 mmol) in dry toluene (50 mL) was heated to reflux for 48 h.The RM was concentrated under reduced pressure to give the crude productwhich was purified by CC to afford mixture of diastereomers (0.8 g, 83%,as off white solid). Diastereomers separation was done by reverse phaseprep HPLC method. Major isomer was characterized as cis diastereomer.

cis-isomer (SC-110, SC-111): 1H NMR (400 MHz, DMSO-d₆, δ ppm): 1.07-1.10(2H), 1.23-1.26 (2H), 1.45-1.47 (4H), 1.71-1.75 (1H), 2.04-2.10 (1H),2.18-2.24 (1H), 2.30-2.34 (1H), 3.67-3.72 (1H), 3.67-3.72 (1H),3.94-3.99 (1H), 4.74-4.78 (1H), 7.94-7.99 (1H), 8.03 (s, 1H), 8.16-8.19(1H), 8.22-8.24 (1H).

Two enantiomers of this single diastereomer were separated by chiralprep HPLC using a CHIRALPAK IC column and EtOH/DEA (100/0.1) as mobilephase to obtain two cis enantiomers SC-110 and SC-111.

SC-110: (0.162 g, off white solid, 1^(st) eluted enantiomer).

SC-111 (0.119 g, off white solid, 2^(nd) eluted enantiomer).

2-Methyl-5-[[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-pyridine(Example 20) Step 1:(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methylmethanesulfonate

To a solution of(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methanol(1.5 g g, 4.4 mmol, 1 eq) in DCM (35 mL) was added TEA (1.9 mL, 12.87mmol, 3 eq) followed by methane sulfonyl chloride (0.64 mL, 8.2 mmol,1.5 eq) at 0° C. Then the RM was stirred at the same temperature for 1h. The reaction was monitored by TLC. The RM was diluted with DCM (50mL) and washed with water (3×20 mL), brine (20 mL), dried over Na₂SO₄and concentrated under reduced pressure to give crude(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methylmethanesulfonate (1.28 g, 82%) as yellow liquid which was used for thenext step without further purification.

Step 2:2-Methyl-5-[[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-pyridine

To a stirring solution of 6-methyl-pyridine-3-ol (0.518 g, 4.7 mmol, 1eq) in DMF (10 mL), at 0° C. under N₂ was added NaH (60% in mineral oil)(0.259 g, 6.49 mmol, 1.5 eq) portion wise and stirred at RT for 30 min.The RM was again cooled to 0° C. and(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methylmethanesulfonate (1.8 g, 4.3 mmol, 1.0 eq) (dissolved in 10 mL of DMF)was added. The RM was stirred at RT for 16 h. After completion of thereaction it was quenched with crushed ice and diluted with EtOAc (200mL). The organic layer was separated, washed with chilled water (3×20mL), brine (50 mL) dried over Na₂SO₄ and concentrated under reducedpressure. Crude product was purified by CC to afford pure2-methyl-5-[[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-pyridine(0.45 g, 75%) as a white solid.

Separation of diastereoisomers was done using reverse phase prep HPLCmethod. Major isomer was characterized as cis diastereomer (SC-112,SC-113) and minor isomer as trans (SC-114, 0.023 g).

trans-isomer (SC-114): 1H NMR (400 MHz, DMSO-d₆, δ ppm): 1.15 (s, 3H),1.57-1.63 (1H), 1.71-1.80 (1H), 2.07-2.09 (1H), 2.13-2.19 (1H), 2.23 (s,3H), 3.83-3.87 (1H), 3.98-4.06 (3H), 4.34-4.37 (1H), 7.16-7.19 (1H),7.28-7.31 (1H), 7.94-7.98 (1H), 8.07 (s, 1H), 8.15-8.16 (1H), 8.20-8.24(2H).

cis-isomer (SC-112, SC-113): 1H NMR (400 MHz, DMSO-d₆, δ ppm): 1.38-1.42(4H), 1.58-1.62 (1H), 1.84-1.91 (1H), 1.96-2.04 (1H), 2.37 (s, 3H),3.52-3.58 (1H), 3.80-3.85 (1H), 3.86-3.93 (1H), 3.95-4.04 (2H),7.13-7.16 (1H), 7.25-7.28 (1H), 7.94-7.99 (1H), 8.03 (s, 1H), 8.11-8.12(1H), 8.16-8.18 (1H), 8.22-8.25 (1H).

Two enantiomers of cis diastereomer were separated by chiral prep HPLCusing a CHIRALPAK IA column and EtOH/DEA (100/0.1) as mobile phase toobtain two cis enantiomers SC-112 and SC-113.

SC-112: (0.123 g, off white solid, 1^(st) eluted enantiomer).

SC-113 (0.105 g, off white solid, 2^(nd) eluted enantiomer).

3-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(Example 21)

Step 1: (5-(trifluoromethyl)pyridin-3-yl)methanol

To a stirred solution of 5-(trifluoromethyl)nicotinic acid (0.5 g, 2.61mmol, 1 eq) in benzene (20 mL) was added TEA (0.44 mL, 3.14 mmol, 1.2eq) followed by ethylchloroformate (0.28 mL, 2.87 mmol, 1.1 eq) at RTand stirred for 1 h. The resulting precipitate was filtered and thefiltrate was concentrated to afford mixed anhydride. This was usedimmediately in the next step.

To a stirred solution of LAH (0.109 g, 2.87 mmol, 1.1 eq) in THF (10 mL)was added above mixed anhydride in THF (10 mL) slowly at −78° C. and themixture was stirred for 1 h at the same temperature. TLC showedcompletion of the reaction. Then the reaction mass was quenched with H₂Oand stirred for 30 min and the mixture was extracted with EtOAc (2×15mL), washed with brine (10 mL), dried over Na₂SO₄ and concentrated. Thecrude product was purified by flash CC to afford(5-(trifluoromethyl)pyridin-3-yl)methanol (0.25 g, 54%) as yellow oil.

Step 2: 5-(trifluoromethyl)nicotinaldehyde

To a stirred solution of 5-(trifluoromethyl)pyridin-3-yl)methanol (0.2g, 1.12 mmol, 1 eq) in DCM (6 mL) was added PCC (0.364 g, 1.68 mmol, 1.5eq) and the mixture was stirred for 16 h at RT. TLC showed completion ofthe reaction. Then the reaction mass was filtered on celite bed and thefiltrate volume was reduced to 10% with N₂ (aldehyde was volatile) toafford 5-(trifluoromethyl)nicotinaldehyde (150 mg). This crude materialwas used in the next step without further purification.

Step 3: 2-(5-(trifluoromethyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ol

Conc H₂SO₄ (0.7 mL) was added drop wise to an ice-cold mixture of5-(trifluoromethyl)nicotinaldehyde (1.5 g, 8.5 mmol, 1 eq) and3-butene-1-ol (1.6 mL, 17.1 mmol, 2 eq), the RM was stirred at RT for 16h. TLC showed completion of the reaction. Then the RM was poured intoice, basified with sat NaHCO₃ solution and extracted with DCM (2×50 mL),washed with brine (20 mL), dried over anhydr. Na₂SO₄, concentrated underreduced pressure. The crude product was purified by CC to afford2-(5-(trifluoromethyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ol (0.5 g, 24%)as yellow liquid.

Step 4: 2-(5-(trifluoromethyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

Methanesulfonyl chloride (0.21 mL, 2.6 mmol, 1.3 eq) was added to anice-cold solution of2-(5-(trifluoromethyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ol (0.5 g, 2mmol, 1 eq) and TEA (0.42 mL, 3 mmol, 1.5 eq) in DCM (20 mL), and the RMwas stirred at the same temperature for 2 h. Then the RM was quenchedwith H₂O and extracted with DCM (2×20 mL), combined organic layer wasdried over anhydr. Na₂SO₄ and concentrated to afford2-(5-(trifluoromethyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (0.65 g) as a brown liquid. This crude product was usedin the next step with out any purification.

Step 5:3-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

K₂CO₃ (1.24 g, 9 mmol, 3 eq) was added to a solution of2-(5-(trifluoromethyl)pyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (0.65 g 2 mmol, 1 eq) and 3-trifluoromethylthiol (0.41mL, 3 mmol, 1.5 eq) in DMF (15 mL), and the reaction mass was heated to80° C. and stirred for 2 h. Then the RM was cooled to RT and quenchedwith ice. The aq. layer was extracted with EtOAc (2×30 mL), combinedorganic layer was dried over anhydr. Na₂SO₄ and concentrated underreduced pressure to yield crude mass which was then purified by flash CCto afford3-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(0.55 g, 68%) as pale yellow oil.

Step 6:3-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred ice cold solution of3-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(0.55 g, 1.35 mmol, 1 eq) in THF: H₂O (3:1) (20 mL) was added Oxone(3.31 g, 5.4 mmol, 4 eq) and the RM was stirred at RT for 1 h. Then theRM was diluted with H₂O, extracted with EtOAc (2×30 mL), combinedorganic layer was washed with H₂O (30 mL), brine (30 mL), dried overanhydr. Na₂SO₄ and evaporated under reduced pressure to get crudeproduct, which was further purified by flash CC to afford3-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)-phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(0.55 g, 93%) as white solid.

Step 7:3-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)pyridine

To a stirred solution of3-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(0.6 g, 1.3 mmol, 1 eq) in THF (20 mL) was added t-BuOK (0.612 g, 5.4mmol, 4 eq), 18-crown-6 (0.686 g, 2.6 mmol, 2 eq), followed by Mel (0.41mmol, 6.5 mmol, 5 eq) at −78° C. The reaction mass was allowed to RTgradually and stirred at RT for 2 h. Then the reaction was diluted withH₂O, extracted with EtOAc (2×35 mL), combined organic layer was washedwith H₂O (20 mL), brine (20 mL), dried over anhydr. Na₂SO₄, evaporatedunder reduced pressure to get crude product which was further purifiedby flash CC to afford3-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)pyridine(0.5 g) as a single diasteroisomer which was confirmed as cisdiastereomer by NMR.

cis-isomer (SC-115, SC-116): 1H NMR (400 MHz, DMSO-d₆, δ ppm): 1.48-1.51(4H), 1.87-1.98 (2H), 2.12-2.17 (1H), 3.71-3.77 (1H), 4.08-4.12 (1H),4.74-4.78 (1H), 7.92-7.96 (1H), 8.06 (s, 1H), 8.11 (s, 1H), 8.17-8.22(2H).

Two enantiomers of cis diastereomer were separated by chiral prep HPLCusing a CHIRALPAK IA column and Hexane/EtOAc/DEA (50/25/25) as mobilephase to obtain two cis enantiomers SC-115 and SC-116.

SC-115: (0.146 g, off white solid, 1^(st) eluted enantiomer).

SC-116: (0.188 g, off white solid, 2^(nd) eluted enantiomer).

2-Cyclopropyl-5-[[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-pyridine(Example 22)

To a solution of(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methylmethanesulfonate (0.5 g, 1.2 mmol, 1 eq) in DMF (10 mL) was added6-cyclopropyl-pyridin-3-ol (0.162 g, 1.2 mmol, 1 eq), Cs₂CO₃ (0.97 g,3.0 mmol, 2.5 eq) and the mixture was heated up to 80° C. for 16 h. Thenthe reaction mass was cooled to RT and diluted with H₂O (15 mL),extracted with EtOAc (2×20 mL), washed with H₂O (15 mL), brine (15 mL),dried over Na₂SO₄ and concentrated. The crude product was purified byreverse phase prep. HPLC to give pure2-cyclopropyl-5-((4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methoxy)pyridine(0.60 g) as a single diastereoisomer (cis).

cis-isomer (SC-117, SC-118): 1H NMR (400 MHz, DMSO-d₆, δ ppm): 0.79-0.80(2H), 0.84-0.87 (2H), 1.38-1.42 (4H), 1.58-1.61 (1H), 1.84-1.90 (1H),1.96-2.03 (2H), 3.51-3.58 (1H), 3.80-3.83 (1H), 3.88-3.93 (1H),3.95-4.04 (2H), 7.17-7.19 (1H), 7.23-7.26 (1H), 7.94-7.99 (1H), 8.03 (s,1H), 8.08-8-09 (1H), 8.15-8.18 (1H), 8.22-8.24 (1H).

Two enantiomers of cis racemic were separated by chiral HPLC, usingCHIRALPAK IA column and EtOH/DEA: (100/0.1) as mobile phase to obtaintwo desired cis enantiomers (SC-117 and SC-117).

SC-117: (0.045 g, white solid, 1^(st) eluted enantiomer).

SC-118: (0.035 g, white solid, 2^(nd) eluted enantiomer).

3-Fluoro-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 23) Step 1: 5-bromo-3-fluoro-N-methoxy-N-methylpicolinamide

To a solution of 5-bromo-3-fluoropicolinic acid (10.0 g, 45.45 mmol, 1eq) in DMF (100 mL), EDC.HCl (12.68 g, 81.70 mmol, 1.8 eq), HOBT (9.82g, 72.68 mmol, 1.6 eq) and TEA (16.88 mL, 117.02 mmol, 2.6 eq) was addedat RT. After stirring the RM at RT for 10 min MeNH(OMe) (5.66 g, 58.95mmol, 1.3 eq) was added and the mixture was stirred at RT for 16 h.After completion of reaction (monitored by TLC), RM was diluted withwater (150 mL) and extracted with EtOAc (3×150 mL). The organic layerwas washed with brine (100 mL), dried over Na₂SO₄, filtered andevaporated under reduced pressure to get the crude product which waspurified by CC to afford 5-bromo-3-fluoro-N-methoxy-N-methylpicolinamide(6.0 g, 50%) as deep brown liquid.

Step 2: 5-bromo-3-fluoropicolinaldehyde

To a solution of 5-bromo-3-fluoro-N-methoxy-N-methylpicolinamide (8.0 g,30.41 mmol eql) in THF (70 mL), the LAH solution (1M in THF) (15.2 mL,15.2 mmol, 0.5 eq) was added at −70° C. for 15 min. Reaction wascontinued at the same temperature for another 2 h. After completion ofreaction (monitored by TLC), RM was quenched with sat. Na₂SO₄ solutionand extracted with EtOAc (3×250 mL). The organic layer was washed withwater (300 mL), brine (200 mL), dried over Na₂SO₄, filtered andevaporated under reduced pressure to get the crude. The crude waspurified by CC to afford 5-bromo-3-fluoropicolinaldehyde (5.5 g, 88.70%)as a brown gum.

Step 3: 2-(5-bromo-3-fluoropyridin-2-yl)tetrahydro-2H-pyran-4-ol

Conc H₂SO₄ (2.7 mL) was added drop wise to an ice-cold mixture of3-buten-1-ol (4.75 mL, 52.84 mmol, 2 eq) and5-bromo-3-fluoropicolinaldehyde (5.5 g, 26.96 mmol, 1 eq). The RM wasallowed to warm to RT slowly and stirred for 16 h. Then the RM waspoured into ice H₂O, basified with sat. NaHCO₃ solution and extractedwith DCM (2×100 mL), combined organic layer was dried over anhydr.Na₂SO₄, concentrated under reduced pressure. The crude product waspurified by CC to afford2-(5-bromo-3-fluoropyridin-2-yl)tetrahydro-2H-pyran-4-ol (1.4 g, 20%) asdeep brown liquid.

Step 4: 2-(5-bromo-3-fluoropyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

Methanesulfonyl chloride (0.62 mL, 7.6 mmol, 1.5 eq) was added to anice-cold solution of2-(5-bromo-3-fluoropyridin-2-yl)tetrahydro-2H-pyran-4-ol (1.4 g, 5.1mmol, 1 eq) and TEA (2.2 mL, 15.32 mmol, 3 eq) in DCM (5 mL), the RM wasstirred at the same temperature and for 2 h. The RM was quenched withH₂O. The aq. layer was extracted with DCM (2×100 mL), combined organiclayer was washed with water and brine and dried over anhydr. Na₂SO₄,concentrated under reduced pressure to yield crude product which waspurified by CC to afford2-(5-bromo-3-fluoropyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (1.5 g, 83%) as colorless oil.

Step 5:5-bromo-3-fluoro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

K₂CO₃ (1.75 g, 12.70 mmol, 3 eq) was added to the solution of2-(5-bromo-3-fluoropyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (1.5 g 4.234 mmol, 1 eq), lithium iodide (0.56 g, 4.2mmol) and 3-trifluoromethylthiol (0.9 mL, 6.352 mmol, 1.5 eq) in DMF (30mL). The RM was stirred at 80° C. for 2 h. Then the RM was cooled to RTand then quenched with ice. The aq. layer was extracted with EtOAc(2×150 mL), combined organic layer was dried over anhydr. Na₂SO₄ andconcentrated under reduced pressure to give crude product which was thenpurified by CC to afford5-bromo-3-fluoro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(1.3 g, 72%) as pale yellow oil.

Step 6:5-bromo-3-fluoro-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred ice cold solution of5-bromo-3-fluoro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(1.4 g, 3.2 mmol, 1 eq) in THF: H₂O (3:1) oxone (7.8 g, 12.83 mmol, 4eq) was added and RM was stirred at RT for 2 h. After completion RM wasevaporated and residue was diluted with water and extracted with EtOAc.The combined organic layer was washed with water, brine and dried overanhydr. Na₂SO₄. The solvent was evaporated under reduced pressure to getcrude product which was further purified by CC to afford5-bromo-3-fluoro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(1.0 g, 88%) as white solid.

Step 6:5-bromo-3-fluoro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred solution of5-bromo-3-fluoro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(0.35 g, 0.74 mmol, 1 eq) in dry THF (20 mL), t-BuOK (0.33 g, 2.9 mmol,4 eq) and 18-crown-6 (0.78 g, 2.9 mmol, 4 eq) was added at −78° C. underAr and stirred for 5 min. Then methyl iodide (0.53 g, 3.7 mmol, 4 eq)was added at the same temperature and the mixture was stirred for 1 h.The RM was allowed to stir for 1 h at RT. The RM was quenched with waterand extracted with EtOAc (3×50 mL). The combined organic layer waswashed with sat. brine and dried over anhydr. Na₂SO₄ and evaporatedunder reduced pressure to get crude product which was further purifiedby CC to afford5-bromo-3-fluoro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-tetrahydro-2H-pyran-2-yl)pyridine(0.68 g, 62%) as off white solid.

Step 7:3-fluoro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine

To a stirred solution of5-bromo-3-fluoro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(0.68 g, 1.41 mmol, 1 eq) in DMSO (10 mL) was added sodiummethanesulfinate (0.14 g, 1.41 mmol, 1.2 eq), and L-proline sodium salt(0.038 g, 0.281 mmol, 0.2 eq). The RM was degassed for 10 min, then CuI(0.028 g, 0.15 mmol, 0.1 eq) was added and the RM was heated to 100° C.for 16 h in a sealed tube. After completion of reaction (monitored byTLC), the reaction mass was diluted with H₂O (40 mL), extracted withEtOAc (2×50 mL), organic layer was washed with H₂O (60 mL), brine (60mL), dried over anhydr. Na₂SO₄, filtered and evaporated under reducedpressure to get crude product which was further purified by flash CC toafford3-fluoro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridineas single diastereomer and this was considered as cis (determined by NMRexperiments).

cis-isomer (SC-119, SC-120): 1H NMR (400 MHz, CDCl₃, δ ppm): 1.22-1.26(1H), 1.59-1.63 (4H), 1.79-1.82 (1H), 2.31-2.39 (1H), 2.47-2.53 (1H),3.12 (s, 3H), 3.74-3.80 (1H), 4.17-4.22 (1H), 4.94-4.97 (1H), 7.72-7.74(1H), 7.92-7.94 (2H), 8.06-8.08 (1H), 8.13 (s, 1H), 8.94 (s, 1H).

Enantiomers of cis diastereomer were directly separated in normal phasechiral prep HPLC using a CHIRALPAK IA column and EtOH/DEA: (100/0.1) toobtain two cis enantiomers (SC-119 and SC-120).

SC-119: (0.022 g, white solid, 1^(st) eluted enantiomer).

SC-120: (0.041 g, white solid, 2^(nd) eluted enantiomer).

2-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-[1,3,4]oxadiazole(Example 24) Step 1: ethyl4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxylate

To a stirred solution of4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxylicacid (5 g, 14.2 mmol) in EtOH (50 mL) was added H₂SO₄ (1 mL) and themixture was heated to reflux for 16 h. Then the RM was concentrated andthe crude product was basified with aq. NaHCO₃ solution, extracted withEtOAc (2×50 mL), washed with brine (30 mL), dried over Na₂SO₄ andconcentrated to afford ethyl4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxylate(4.5 g) as an off white solid. This crude material was used for the nextstep with out any purification.

Step 2:4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide

To a stirred solution of ethyl4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxylate(6 g, 15.8 mmol, 1 eq) in toluene (60 mL) was added hydrazine hydratesolution (1.18 mL, 23.7 mmol, 1.5 eq) and the mixture was heated toreflux for 16 h. Then EtOH was evaporated and the residue was dilutedwith EtOAc (100 mL), washed with H₂O (2×30 mL), brine (30 mL), driedover Na₂SO₄ and concentrated to afford4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(5.3 g, 91%) as white solid.

Step 3:4-methyl-N′-(2,2,2-trifluoroacetyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide

To a stirred solution of4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(1 g, 2.7 mmol, 1 eq) in DCM (30 mL) was added TEA (1.14 mL, 8.19 mmol,3 eq), catalytic amount of DMAP, followed by trifluoroaceticanhydride(0.42 mL, 3.0 mmol, 3 eq) at 0° C. and the mixture was stirred for 2 hat RT. Then the reaction mass was quenched with H₂O and extracted withDCM (2×25 mL), washed with brine (20 mL), dried over Na₂SO₄ andconcentrated. The crude product was purified by CC to afford4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(700 mg) as an off white solid.

Step 4:2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole

To a stirred solution of4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(0.6 g, 1.3 mmol, 1 eq) in toluene (20 mL) was added POCl₃ (3 mL) andheated to reflux for 16 h. Then POCl₃ was evaporated and the crudeproduct was basified with sat. NaHCO₃ solution and extracted with EtOAc(2×20 mL), washed with H₂O (2×10 mL), brine (10 mL), dried over Na₂SO₄and concentrated. The crude product was purified by CC to afford mixtureof diastereomers (300 mg) as an off white solid. This diasteriomericmixture was separated by reverse phase prep. HPLC to get cisdiastereomer (SC-121, SC-122).

cis-isomer (SC-121, SC-122): 1H NMR (400 MHz, CDCl₃, δ ppm): 8.25 (d,J=7.84 Hz, 1H), 8.21 (d, J=7.92 Hz, 1H), 8.07 (s, 1H), 8.0 (t, J=15.7Hz, 1H), 5.15 (dd, J=13.8 Hz, 1H), 4.06 (dd, J=16.48 Hz, 1H), 3.81 (t,J=22.88 Hz, 1H), 2.36 (t, J=24.8 Hz, 1H), 2.14 (m, 1H), 1.98 (d, J=12.8Hz, 1H), 1.48 (s, 4H).

Two enantiomers of cis diastereoisomer was separated by chiral HPLC,using chiralcel OJ-H column and Hexane/EtOH/DEA: (90/10/0.1) as mobilephase to obtain two desired cis enantiomers (SC-121 and SC-122).

SC-121: (61 mg, white solid, 1^(st) eluted enantiomer).

SC-122: (43 mg, white solid, 2^(nd) eluted enantiomer).

2-(Difluoro-methyl)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole(Example 25) Step 1:N′-(2,2-difluoroacetyl)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide

To a stirred solution of4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(1 g, 2.7 mmol, 1 eq) in DCM (30 mL) was added TEA (1.14 mL, 8.2 mmol, 3eq), catalytic amount of DMAP, followed by difluoroaceticanhydride (0.37mL, 3.0 mmol, 3 eq) at 0° C. and the mixture was stirred for 2 h at RT.Then the reaction mass was quenched with H₂O and extracted with DCM(2×25 mL), washed with brine (20 mL), dried over Na₂SO₄ andconcentrated. The crude product was purified by CC to affordN′-(2,2-difluoroacetyl)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(650 mg) as an off white solid.

Step 2:2-(difluoromethyl)-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1,3,4-oxadiazole

To a stirred solution ofN′-(2,2-difluoroacetyl)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(0.65 g, 1.5 mmol, 1 eq) in toluene (22 mL) was added POCl₃ (3.5 mL) andthe mixture was heated to reflux for 16 h. Then POCl₃ was evaporated andthe residue was basified with sat. NaHCO₃ solution and extracted withEtOAc (2×25 mL), washed with H₂O (2×10 mL), brine (15 mL), dried overNa₂SO₄ and concentrated. The crude product was purified by CC to affordmixture of diastereomers (270 mg) as an off white solid. Thisdiasteriomers were separated by reverse phase prep. HPLC to afford onemajor diastereomer which was determined as cis isomer.

cis isomer (SC-123, SC-124): ¹H NMR (400 MHz, DMSO-d₆): δ 8.25 (dd,J=25.64 Hz, 2H), 8.07 (s, 1H), 8.0 (t, J=15.72 Hz, 1H), 7.5 (m, 1H),5.10 (d, J=10.28 Hz, 1H), 4.04 (dd, J=15.6 Hz, 1H), 3.81 (t, J=23.3 Hz,1H), 2.35 (t, J=24.64 Hz, 1H), 2.14 (m, 1H), 1.98 (d, J=13.04 Hz, 1H),1.48 (s, 4H).

Two enantiomers of cis diastereoisomer were separated by chiral HPLC,using chiralpak ID column and Hexane/EtOH/DEA: (90/10/0.1) as mobilephase to obtain two desired cis enantiomers (SC-123 and SC-124).

SC-123: (31.8 mg, white solid, 1^(st) eluted enantiomer).

SC-124: (34.2 mg, white solid, 2^(nd) eluted enantiomer).

2-Isopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole(Example 26) Step 1:N′-isobutyryl-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide

To a stirred solution of4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(1 g, 2.7 mmol, 1 eq) in DCM (30 mL) was added TEA (1.14 mL, 8.2 mmol, 3eq), followed by isobutyrylchloride (0.32 mL, 3.0 mmol, 3 eq) at 0° C.and the mixture was stirred for 2 h at RT. Then the reaction mass wasquenched with H₂O and extracted with DCM (2×25 mL), washed with brine(20 mL), dried over Na₂SO₄ and concentrated. The crude product waspurified by CC to affordN′-isobutyryl-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(670 mg) as an off white solid.

Step 2:2-isopropyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1,3,4-oxadiazole

To a stirred solution ofN′-isobutyryl-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(0.6 g, 1.4 mmol, 1 eq) in toluene (20 mL) was added POCl₃ (3 mL) andheated to reflux for 16 h. Then POCl₃ was evaporated and the crude wasbasified with sat. NaHCO₃ solution and extracted with EtOAc (2×25 mL),washed with H₂O (2×10 mL), brine (15 mL), dried over Na₂SO₄ andconcentrated. The crude product was purified by CC to afford mixture ofdiastereomers (260 mg) as an off white solid. This diasteriomers wereseparated by reverse phase prep. HPLC to afford one major diastereomerwhich was determined as cis isomer by NMR.

cis-isomer (SC-125, SC-126): ¹H NMR (400 MHz, DMSO-d₆): δ 8.25 (d, J=7.8Hz, 1H), 8.2 (d, J=7.88, 1H) 8.06 (s, 1H), 7.99 (t, J=15.76 Hz, 1H),4.94 (dd, J=13.8 Hz, 1H), 4.01 (dd, J=17.04 Hz, 1H), 3.77 (t, J=22.88Hz, 1H), 3.32 (m, 1H), 2.32 (m, 1H), 2.11 (m, 1H), 1.90 (d, J=12.92 Hz,1H), 1.48 (s, 4H), 1.29 (d, J=7.6 Hz, 6H).

Two enantiomers of cis diastereoisomer were separated by chiral HPLC,using chiralpak IC column and Hexane/EtOH/DEA: (80/20/0.1) as mobilephase to obtain two desired cis enantiomers (SC-125 and SC-126)

SC-125: (36 mg, white solid, 1^(st) eluted enantiomer).

SC-126: (36 mg, white solid, 2^(nd) eluted enantiomer).

2-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole(Example 27) Step 1:N′-(cyclopropanecarbonyl)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide

To a stirred solution of4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(2 g, 5.5 mmol, 1 eq) in DMF (30 mL), was added HATU (2.7 g, 7.1 mmol,1.3 eq), DIPEA (2.38 mL, 13.7 mmol, 2.5 eq) followed bycyclopropylcarboxylic acid (0.56 g, 6.6 mmol, 1.2 eq) and the mixturewas stirred for 3 h. Then the RM was quenched with ice and extractedwith EtOAc (2×50 mL), washed with H₂O (2×20 mL), brine (20 mL), driedover Na₂SO₄ and concentrated. The crude product was purified by CC toaffordN′-(cyclopropanecarbonyl)-4-methyl-4-((3-(trifluoromethyl)-phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(1.4 g, 60%) as an off white solid.

Step 2:2-cyclopropyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1,3,4-oxadiazole

To a stirred solution ofN′-(cyclopropanecarbonyl)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(3.5 g, 8.1 mmol, 1 eq) in toluene (60 mL) was added POCl₃ (14 mL) andthe mixture was heated to reflux for 16 h. Then POCl₃ was evaporated andthe residue was basified with sat. NaHCO₃ solution and extracted withEtOAc (2×60 mL), washed with H₂O (2×20 mL), brine (20 mL), dried overNa₂SO₄ and concentrated. The crude product was purified by CC to affordmixture of diastereomers (2 g) as an off white solid. This diasteriomerswere separated by reverse phase prep. HPLC to afford one cisdiastereomer and one trans diastereomer (233 mg). The relativestereochemistry of both isomers was confirmed by NOE experiments.

trans-isomer (SC-127): ¹H NMR (400 MHz, DMSO-d₆): δ 8.26 (m, 2H), 8.11(s, 1H), 7.98 (t, J=15.56 Hz, 1H), 5.3 (dd, J=10.04 Hz, 1H), 4.14 (t,J=20.48 Hz, 1H), 3.92 (m, 1H), 2.46 (m, 1H), 2.25 (m, 1H), 2.11 (m, 2H)1.83 (m, 1H), 1.17 (m, 5H), 1.07 (m, 2H).

cis-isomer (SC-128, SC-129): ¹H NMR (400 MHz, DMSO-d₆): δ 8.24 (d,J=7.76 Hz, 1H), 8.20 (d, J=7.84 Hz, 1H), 8.06 (s, 1H), 7.99 (t, J=15.6Hz, 1H), 4.89 (d, J=10.6 Hz, 1H), 4.0 (dd, J=16.52 Hz, 1H), 3.75 (t,J=23.24 Hz, 1H), 2.23 (m, 2H), 2.08 (m, 1H), 1.87 (d, J=12.7 Hz, 1H),1.45 (s, 4H), 1.14 (m, 2H), 0.98 (m, 2H).

Two enantiomers of cis isomer were separated by chiral HPLC, usingchiral pack 1A column and Hexane/EtOH/DEA: (80/20/0.1) as mobile phaseto obtain two desired cis enantiomers (SC-128 and SC-129).

SC-128: (552 mg, white solid, 1^(st) eluted enantiomer).

SC-129: (550 mg, white solid, 2^(nd) eluted enantiomer).

3-Chloro-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 28) Step 1: 5-bromo-3-chloro-N-methoxy-N-methylpicolinamide

To a solution of 5-bromo-3-chloropicolinic acid (15.0 g, 63.424 mmol, 1eq) in DMF (150 mL), EDCl (17.72 g, 114.16 mmol, 1.8 eq), HOBT (13.71 g,101.47 mmol, 1.6 eq) and DIPEA (23.0 mL, 164.9 mmol, 2.6 eq) was addedat RT. After stirring the RM at RT for 10 min MeNH(OMe) (7.95 g, 82.45mmol, 1.3 eq) was added and the mixture was stirred at RT for 16 h.After completion of reaction (monitored by TLC), RM was diluted withwater (250 mL) and extracted with EtOAc (3×250 mL). The organic layerwas washed with brine (500 mL), dried over Na₂SO₄, filtered andevaporated under reduced pressure to get the crude product which waspurified by flash CC to afford5-bromo-3-chloro-N-methoxy-N-methylpicolinamide (9.0 g, 51%) as whitesolid.

Step 2: 5-bromo-3-chloropicolinaldehyde

To a solution of 5-bromo-3-chloro-N-methoxy-N-methylpicolinamide (9.0 g,32.3 mmol, 1 eq) in THF (100 mL), the LAH solution (1M in THF) (16.12mL, 16.1 mmol, 0.5 eq) was added at −70° C. for 15 min. Reaction wascontinued at the same temperature for another 2 h. After completion ofreaction (monitored by TLC), RM was quenched with sat. Na₂SO₄ solutionand extracted with EtOAc (3×250 mL). The organic layer was washed withwater (500 mL), brine (500 mL), dried over Na₂SO₄, filtered and thesolvent was evaporated under reduced pressure to get the crude productwhich was purified by flash CC to afford 5-bromo-3-chloropicolinaldehyde(5.0 g, 71%) as brown gum.

Step 3: 2-(5-bromo-3-chloropyridin-2-yl)tetrahydro-2H-pyran-4-ol

Conc. sulfuric acid (5.0 mL) was added to an ice-cold (0° C.) mixture of5-bromo-3-chloropicolinaldehyde (5 g, 22.7 mmol, 1 eq) and 3-butene-1-ol(4.1 mL, 45.5 mmol, 2 eq) and the mixture was stirred for 16 h at RT.The reaction mass was poured into crushed ice, neutralized by additionof solid NaHCO₃, extracted with EtOAc (2×100 mL) and the organic layerwas washed with brine (150 ml). Combined organic layer was dried overanhydr. Na₂SO₄, filtered and the solvent was evaporated under reducedpressure to get crude mass which was then purified by combiflash CC toafford 2-(5-bromo-3-chloropyridin-2-yl)tetrahydro-2H-pyran-4-ol (1.1 g,17%) as colorless oil.

Step 4:2-(5-bromo-3-chloropyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

Methanesulfonyl chloride (0.55 mL, 7.2 mmol, 1.5 eq) was added to anice-cold solution of2-(5-bromo-3-chloropyridin-2-yl)tetrahydro-2H-pyran-4-ol (1.4 g, 4.8mmol, 1 eq) and TEA (2.0 mL, 14.4 mmol, 3 eq) in DCM (15 mL). The RM wasstirred at the same temperature for 3 h. The RM was quenched with H₂O(50 mL). The aq. layer was extracted with DCM (2×100 mL), combinedorganic layer was dried over anhydr. Na₂SO₄, filtered and the solventwas evaporated under reduced pressure to give crude product which waspurified by combiflash CC to afford2-(5-bromo-3-chloropyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (1.6 g, 90%) as colorless oil.

Step 5:5-bromo-3-chloro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

K₂CO₃ (1.79 g, 13.0 mmol, 3 eq) was added to the solution of2-(5-bromo-3-chloropyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (1.6 g, 4.3 mmol, 1 eq) and triflouromethylbenzenethiol(1.15 g, 6.5 mmol, 1.5 eq) in DMF (20 mL). The RM was stirred at 60° C.for 2 h. Then the RM was cooled to RT and then quenched with ice. The RMwas extracted with EtOAc (2×50 mL) and combined organic layers werewashed repeatedly with cold water (75 mL) and brine (75 mL). Combinedorganic layer was dried over anhydr. Na₂SO₄, filtered and the solventwas evaporated under reduced pressure to give crude mass which was thenpurified by combiflash CC to afford5-bromo-3-chloro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(1.2 g, 61.5%) as white solid.

Step 6:5-bromo-3-chloro-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred ice cold solution of5-bromo-3-chloro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(1.1 g, 2.4 mmol, 1 eq) in THF: H₂O (3:1) (50 mL) oxone (5.97 g, 9.7mmol, 4 eq) was added and RM was stirred at RT for 2 h. After completionof the reaction it was diluted with water (50 mL) and extracted withEtOAc (3×75 mL). The combined organic layer was washed with water (100mL), sat. brine (100 mL), dried over Na₂SO₄, filtered and the solventwas evaporated under reduced pressure to get crude product, which wasfurther purified by combiflash CC to afford5-bromo-3-chloro-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(1.1 g, 85%) as white solid.

Step 7:5-bromo-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred solution of5-bromo-3-chloro-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(1.0 g, 2.1 mmol, 1 eq) in THF (40 mL) was added t-BuOK (0.93 g, 8.3mmol, 4 eq), 18-crown-6 (2.2 g, 8.3 mmol, 4 eq), followed by Mel (0.646ml, 10.33 mmol, 5 eq) at −78° C. and stirred for 1 h at the sametemperature. Then reaction mass was allowed to RT gradually and stirredat RT for further 1 h. After completion of reaction (monitored by TLC),the reaction was diluted with H₂O (50 mL), extracted with EtOAc (2×75mL). Combined organic layer was washed with H₂O (100 mL), brine (100mL), dried over anhydr. Na₂SO₄, filtered and the solvent was evaporatedunder reduced pressure to get crude product which was further purifiedby combiflash CC to afford5-bromo-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)-phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(0.75 g, 74%) as off white solid.

Step 8:3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine

To a stirred solution of5-bromo-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(0.75 g, 1.51 mmol, 1 eq) in DMSO (7 mL) was added sodiummethanesulfinate (0.184 g, 1.81 mmol, 1.2 eq), and L-proline sodium salt(0.041 g, 0.30 mmol, 0.2 eq). The RM was degassed for 10 min and thenCuI (28.6 mg, 0.15 mmol, 0.1 eq) was added and the RM was heated to 100°C. for 16 h in a sealed tube. After completion of reaction (monitored byTLC), the reaction mass was diluted with H₂O (40 mL), extracted withEtOAc (2×50 mL), organic layer was washed with H₂O (60 mL), brine (60mL), dried over anhydr. Na₂SO₄, filtered and evaporated under reducedpressure to get crude product which was further purified by combiflashCC to afford3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)-sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridineas mixture of diasteriomers (95: 5 diastereomeric ratio, 460 mg). Themajor diastereomer was isolated by reverse phase prep HPLC and this wasconsidered as cis (determined by NMR experiments). cis-isomer (SC-130,SC-131): 1H NMR (400 MHz, CDCl₃, δ ppm): 1.45-1.50 (4H), 1.71-1.75 (1H),2.10-2.17 (1H), 2.58-2.67 (1H), 3.95 (s, 3H), 3.73-3.79 (1H), 4.00-4.04(1H), 5.02-5.04 (1H), 7.94-7.97 (1H), 8.07 (s, 1H), 8.18-8.20 (1H),8.22-8.24 (1H), 8.46-8.47 (1H), 9.00-9.01 (1H).

Enantiomers of cis diastereomer were directly separated in normal phasechiral prep HPLC using a CHIRALCEL OJ-H column and MeOH/DEA: (100/0.1)to obtain two cis enantiomers (SC-130 and SC-131).

SC-130: (0.105 g, white solid, 1^(st) eluted enantiomer)/specificrotation [α]_(D) ^(24.0) −26.6° (c 0.70; DCM).

SC-131: (0.110 g, white solid, 2^(nd) eluted enantiomer)/specificrotation [α]_(D) ^(24.3) +34.9° (c 0.58; DCM).

2-Cyclopropyl-5-[[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-pyrazine(Example 29) Step 1:2-chloro-5-((4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methoxy)pyrazine

To a stirred solution of(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methanol(1 g, 2.9 mmol, 1 eq) in toluene (20 mL) was added 2,5-dichloro-pyrazine(0.3 mL, 2.9 mmol, 1 eq), Cs₂CO₃ (1.8 g, 5.9 mmol, 2 eq) and the mixturewas heated to reflux for 48 h. Then the reaction mass was cooled to RT,diluted with H₂O (15 mL), extracted with EtOAc (2×30 mL), washed withbrine (20 mL), dried over Na₂SO₄ and concentrated. The crude product waspurified by CC to afford2-chloro-5-((4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methoxy)pyrazine(0.7 g, 53%) as yellow gum.

Step 2:2-cyclopropyl-5-((4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methoxy)pyrazine

To a stirred solution of2-chloro-5-((4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)methoxy)pyrazine(1.6 g, 3 mmol, 1 eq.) in toluene/H₂O (20 mL) was added Cs₂CO₃ (2.9 g,8.9 mmol, 3 eq), potassium cyclopropyl trifluoroborate (0.526 g, 3 mmol,1 eq), and the solution was degassed with Ar for 10 min. Thendi-(1-adamantyl)-n-butylphosphine (0.032 g, 0.089 mmol, 0.03 eq.) andPd(OAc)₂ (0.015 g, 0.08 mmol, 0.0.2 eq) were added. Then the RM washeated to 120° C. for 16 h in a sealed tube. After completion of thereaction (monitored by TLC), the RM was filtered on celite bed, washedwith EtOAc (2×35 mL), the filtrate was washed with H₂O (25 mL), brine(25 mL), dried over Na₂SO₄ and concentrated. The crude product waspurified by reverse phase prep. HPLC to give pure cis-diastereomer (0.30g).

cis-isomer (SC-132, SC-133): ¹H NMR (400 MHz, CDCl₃): 0.90-0.97 (4H),1.49-1.54 (4H), 1.62-1.66 (1H), 1.94-2.06 (2H), 2.18-2.26 (1H),3.55-3.61 (1H), 3.80-3.84 (1H), 4.03-4.07 (1H), 4.25-4.33 (2H),7.71-7.75 (1H), 7.92-7.95 (1H), 8.03-8.06 (1H), 8.08 (s, 1H), 8.12 (bs,1H).

Two enantiomers of cis isomer were separated by chiral HPLC, usingchiral pack-IC column and EtOH/DEA: (100/0.1) as mobile phase to obtaintwo desired cis enantiomers (SC-132 and SC-133).

SC-132: (0.075 g, white solid, 1^(st) eluted enantiomer).

SC-133: (0.055 g, white solid, 2^(nd) eluted enantiomer).

3-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 17) Step 1: 2-(5-bromopyridin-3-yl)tetrahydro-2H-pyran-4-ol

Conc. sulfuric acid (3.8 mL) was added to an ice-cold (0° C.) mixture of5-bromonicotinaldehyde (5 g, 26.9 mmol, 1 eq) and 3-butene-1-ol (4.6 mL,53.8 mmol, 2 eq) and the mixture was stirred for 14 h at RT. Thereaction mass was poured into crushed ice, neutralized by addition ofsolid NaHCO₃, extracted with DCM (2×150 mL) and the organic layer waswashed with brine. Combined organic layer was dried over anhydr. Na₂SO₄,concentrated under reduced pressure to give crude mass which was thenpurified by CC to afford 2-(5-bromopyridin-3-yl)tetrahydro-2H-pyran-4-ol(4.6 g, 67%) as a colorless oil.

Step 2: 2-(5-bromopyridin-3-yl)tetrahydro-2H-pyran-4-yl methanesulfonate

Methanesulfonyl chloride (2.7 mL, 26.8 mmol, 1.5 eq) was added to anice-cold solution of 2-(5-bromopyridin-3-yl)tetrahydro-2H-pyran-4-ol(4.6 g, 17.9 mmol, 1 eq) and TEA (7.5 mL, 53.7 mmol, 3 eq) in DCM (5mL), the RM was stirred at the same temperature and for 2 h. The RM wasquenched with H₂O. The aq. layer was extracted with DCM (2×100 mL),combined organic layer was dried over anhydr. Na₂SO₄, concentrated underreduced pressure to give crude product which was purified by CC toafford 2-(5-bromopyridin-3-yl)tetrahydro-2H-pyran-4-yl methanesulfonate(0.6 g, 92%) as a colorless oil.

Step 3:3-bromo-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

K₂CO₃ (3.8 g, 28.0 mmol, 2 eq) was added to the solution of2-(5-bromopyridin-3-yl)tetrahydro-2H-pyran-4-yl methanesulfonate (4.7 g,14.0 mmol, 1 eq) and trifloromethylbenzenethiol (2.5 g, 14.0 mmol, 1.2eq) in DMF (10 mL). The RM was stirred at 100° C. for 16 h. Then the RMwas cooled to RT and then quenched with ice. The aq. layer was extractedwith EtOAc (2×100 mL) and washed repeatedly with cold water and brine.Combined organic layer was dried over anhydr. Na₂SO₄, concentrated underreduced pressure to give crude mass which was then purified by CC toafford3-bromo-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(3.3 g, 57%) as a white solid.

Step 4:3-bromo-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred ice cold solution of3-bromo-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(3.3 g, 7.9 mmol, 1 eq) in THF:H₂O (3:1) oxone (19.4 g, 31.6 mmol, 4 eq)was added and RM was stirred at RT for 2 h. The RM was diluted withwater and extracted with EtOAc. The combined organic layer was washedwith water, sat. brine and dried over anhydr. Na₂SO₄ and evaporatedunder reduced pressure to get crude product which was further purifiedby CC to afford3-bromo-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(2.7 g, 66%) as a white solid.

Step 5:3-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred solution of3-bromo-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(1.35 g, 3.0 mmol, 1 eq) in THF (20 mL) was added t-BuOK (0.68 g, 6.0mmol, 2 eq), 18-crown-6 (1.6 g, 6.0 mmol, 2 eq), followed by Mel (1.5 g,11.1 mmol, 5 eq) at −78° C. and stirred for 1 h at the same temperature.Then reaction mass was allowed to RT gradually and stirred for further 1h. Then the RM was diluted with H₂O, extracted with EtOAc (2×35 mL),combined organic layer was washed with H₂O (20 mL), brine (20 mL), driedover anhydr. Na₂SO₄, evaporated under reduced pressure to get crudeproduct which was further purified by CC to afford3-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(0.65 g, 65%) as an off white solid.

Step 6:3-cyclopropyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred solution of3-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(1.5 g, 3.24 mmol, 1 eq) in toluene (45 ml) in a sealed tube was addedNaBr (0.33 g, 3.24 mmol, 1 eq), KF (0.75 g, 12.96 mmol, 4 eq) followedby cyclopropyl borinic acid (0.42 g, 4.86 mmol, 1.5 eq). The mixture wasthen degassed for 15 min and Pd(PPh₃)₄ (0.375 g, 0.324 mmol, 0.1 eq) andX-Phos (0.156 g, 0.324 mmol, 0.1 eq) was added. The RM was degassedagain for 10 min before closing the seal tube tightly. The mixture washeated to 90° C. for 16 h. Then the reaction mass was diluted with H₂O,extracted with EtOAc (2×50 mL), organic layer was washed with H₂O (50mL), brine (50 mL), dried over anhydr. Na₂SO₄ and evaporated underreduced pressure to get crude product which was further purified by CCto afford3-cyclopropyl-5-(4-methyl-4-((3-(trifluoromethyl)-phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridineas a mixture diastereomers (0.45 g). Diastereomers were separated byreverse phase prep. HPLC to obtain pure cis isomer (0.310 g).

cis-isomer (SC-325, SC-326): ¹H NMR (400 MHz, CDCl₃): 0.70-0.73 (2H),0.96-1.02 (2H), 1.46-1.49 (4H), 1.71-1.75 (1H), 1.871.97 (2H), 2.07-2.11(1H), 3.69-3.72 (1H), 4.03-4.07 (1H), 4.55-4.58 (1H), 7.92-9.96 (1H),8.05 (s, 1H), 8.16-8.22 (2H), 8.28-8.31 (2H).

The enantiomers of cis isomer were separated by SFC using a CHIRALPAK IAcolumn to give SC-325 and SC-326.

SC-325: (0.115 g, white solid, 1^(st) eluted enantiomer).

SC-326: (0.124 g, white solid, 2^(nd) eluted enantiomer).

3-Chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)pyridine(Example 30)

Step 1: 1-(5-bromo-3-chloropyridin-2-yl)but-3-en-1-ol

To a stirred solution of 5-bromo-3-chloropicolinaldehyde (8.5 g, 38.6mmol, 1 eq) in THF(135 mL) was added allylbromide (5.0 mL, 90.6 mmol,1.5 eq) and sat. NH₄Cl solution followed by zinc dust (5.0 g, 77.3 mmol,2 eq). After complete addition the RM was stirred for 2 h at RT. Thenthe RM was diluted with water (100 mL) and extracted with EtOAc (3×100mL), dried over anhydr. Na₂SO₄ and evaporated under reduced pressure togive crude product which was purified by CC to afford1-(5-bromo-3-chloropyridin-2-yl)but-3-en-1-ol (4.5 g, 44%) as an offwhite solid.

Step 2: 4-(5-bromo-3-chloropyridin-2-yl)butane-1,2,4-triol

To a stirred solution of 1-(5-bromo-3-chloropyridin-2-yl)but-3-en-1-ol(1.8 g, 6.8 mmol, 1 eq) in a mixture of acetone (38 mL) and water (16mL) was added NMO at 0° C. (1.08 g, 8.91 mmol, 1.3 eq) followed by OsO₄(0.017 g, 0.067 mmol, 0.012 eq) and the mixture was stirred for 16 h atRT. After completion of the reaction the RM was concentrated, dilutedwith EtOAc (100 mL), washed with water (2×50 mL), dried over anhydr.Na₂SO₄, and the solvent was evaporated under reduced pressure to givecrude product as a black oil which was purified by CC to afford4-(5-bromo-3-chloropyridin-2-yl)butane-1,2,4-triol (1.4 g, 70%) as anoff white solid.

Step 3: 5-(5-bromo-3-chloropyridin-2-yl)tetrahydrofuran-3-ol

To a stirred solution of1-(5-bromo-3-chloropyridin-2-yl)butane-1,2,4-triol (7.5 g, 25.3 mmol, 1eq) in DCE (250 mL) was added triflic acid (6 mL) and the mixture washeated to reflux for 16 h. After completion of the reaction (monitoredby TLC), the RM was neutralized with sat. NaHCO₃ solution, extractedwith DCM (2×75 mL), washed with brine (50 mL), dried over Na₂SO₄ andconcentrated to give light yellow oil which was purified by CC to afford5-(5-bromo-3-chloropyridin-2-yl)tetrahydrofuran-3-ol (2.5 g, 36%) as anoff white solid.

Step 4: 5-(5-bromo-3-chloropyridin-2-yl)tetrahydrofuran-3-ylmethanesulfonate

Methanesulfonyl chloride (1.2 mL, 13.5 mmol, 1.5 eq) was added to anice-cold solution of5-(5-bromo-3-chloropyridin-2-yl)tetrahydrofuran-3-ol (2.5 g, 8.99 mmol,1 eq) and TEA (4 mL, 26.96 mmol, 3 eq) in DCM (40 mL). The RM wasstirred at the same temperature and for 2 h. The RM was quenched withH₂O (100 mL). The aq. layer was extracted with DCM (2×200 mL), combinedorganic layer was dried over anhydr. Na₂SO₄, filtered and evaporatedunder reduced pressure to give crude product which was purified by CC toafford 5-(5-bromo-3-chloropyridin-2-yl)tetrahydrofuran-3-ylmethanesulfonate (2.5 g. 42%) as colorless oil.

Step 5:5-bromo-3-chloro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydrofuran-2-yl)pyridine

K₂CO₃ (5.6 g, 40.6 mmol, 3 eq) was added to a solution of5-(5-bromo-3-chloropyridin-2-yl)tetrahydrofuran-3-yl methanesulfonate(4.8 g, 13.48 mmol, 1 eq) and trifloromethylbenzenethiol (3.6 g, 20.2mmol, 1.5 eq) in DMF (60 mL). The RM was stirred at 90° C. for 16 h.Then the RM was cooled to RT and then quenched with ice. The aq. layerwas extracted with EtOAc (2×150 mL), washed repeatedly with cold water(150 ml) and brine (150 mL). Combined organic layer was dried overanhydr. Na₂SO₄, filtered and evaporated under reduced pressure to givecrude mass which was then purified by using CC to afford5-bromo-3-chloro-2-(4-((3-(trifluoromethyl)phenyl)thio)-tetrahydrofuran-2-yl)pyridine(5.2 g, 88%) as a colorless oil.

Step 6:5-bromo-3-chloro-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)pyridine

To a stirred solution of5-bromo-3-chloro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydrofuran-2-yl)pyridine(6.0 g, 13.69 mmol, 1 eq) in THF:H₂O (3:1) (100 mL), oxone (33.6 g, 54.7mmol, 4 eq) was added and the RM was stirred at RT for 1 h. The RM wasdiluted with water (100 mL) and extracted with EtOAc (3×150 mL). Thecombined organic layer was washed with water (100 mL), brine (100 mL),dried over Na₂SO₄, filtered and evaporated under reduced pressure to getcrude product, which was further purified by CC to afford5-bromo-3-chloro-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)pyridine(2.5 g, 39%) as white solid.

Step 7:5-bromo-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)pyridine

To a stirred solution of5-bromo-3-chloro-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)pyridine(1.6 g, 3.40 mmol, 1 eq) in THF (100 mL) was added t-BuOK (1M in THF;5.1 mL; 5.10 mmol, 1.5 eq), 18-crown-6 (1.37 g, 5.10 mmol, 1.5 eq),followed by Mel (0.42 mL, 6.80 mmol, 2 eq) at −100° C. and the mixturewas stirred for 5 min at the same temperature. After completion ofreaction (monitored by TLC), the RM was diluted with H₂O (50 mL),extracted with EtOAc (2×75 ml). Combined organic layer was washed withH₂O (100 mL), brine (100 mL), dried over anhydr. Na₂SO₄, filtered andthe solvent was evaporated under reduced pressure to get crude productwhich was further purified by CC to afford5-bromo-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)pyridine(1.2 g, 73%) as an off white solid.

Step 8:3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)pyridine

To a stirred solution of5-bromo-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)pyridine(1.6 g, 3.30 mmol, 1 eq) in DMSO (30 mL) was added sodiummethanesulfinate (404 mg, 3.96 mmol, 1.2 eq), and L-proline sodium salt(90 mg, 0.661 mmol, 0.2 eq) and the mixture was degassed with N₂ for 10min. CuI (62 mg, 0.330 mmol, 0.1 eq) was added and the RM was heated to100° C. for 16 h in a sealed tube. After completion of reaction(monitored by TLC), the reaction mass was diluted with H₂O (75 mL),extracted with EtOAc (2×75 mL), organic layer was washed with H₂O (60mL), brine (60 mL), dried over anhydr. Na₂SO₄, filtered and the solventwas evaporated under reduced pressure to get crude product which wasfurther purified by CC to afford3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)pyridineas a mixture of diastereoisomers. Diastereomers were separated byreverse phase prep HPLC to give trans isomer (600 mg) and cis isomer(100 mg) and the relative configuration of both isomers was confirmed byNOE experiment.

cis-isomer (SC-150, SC-151): ¹H NMR (400 MHz, DMSO-d₆): δ 8.89 (s, 1H),8.44 (s, 1H), 8.25 (d, J=7.56 Hz, 1H), 8.19 (d, J=7.68 Hz, 1H), 8.11 (s,1H), 7.94 (t, J=15.6 Hz, 1H), 5.52 (t, J=15.16 Hz, 1H), 4.54 (d, J=9.64Hz, 1H), 3.78 (d, J=9.68 Hz, 1H), 3.38 (s, 3H), 3.11 (m, 1H), 2.31 (m,1H), 1.56 (s, 3H).

Two enantiomers of cis isomer was separated by chiral HPLC, using chiralpack 1A column and EtOH/DEA: (100/0.1) as mobile phase to obtain twodesired cis enantiomers (SC-150 and SC-151).

SC-150: (27 mg, white solid, 1^(st) eluted enantiomer).

SC-151: (24 mg, white solid, 2^(nd) eluted enantiomer).

trans-isomer (SC-152, SC-153): ¹H NMR (400 MHz, DMSO-d₆): δ 8.98 (s,1H), 8.45 (s, 1H), 8.35 (d, J=7.8 Hz, 1H), 8.25 (d, J=8.88 Hz, 2H), 7.99(t, J=14.44 Hz, 1H), 5.33 (t, J=14.28 Hz, 1H), 4.47 (d, J=10.28 Hz, 1H),3.91 (d, J=10.28 Hz, 1H), 3.37 (s, 3H), 3.08 (m, 1H), 2.43 (m, 1H), 1.51(s, 3H).

Two enantiomers of trans isomer was separated by chiral HPLC, usingchiral pack 1C column and Hexane/EtOH/DEA: (80/20/0.1) as mobile phaseto obtain two desired cis enantiomers (SC-152 and SC-153).

SC-152: (220 mg, white solid, 1^(st) eluted enantiomer).

SC-153: (210 mg, white solid, 2^(nd) eluted enantiomer).

3-Methyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)pyridine(Example 31)

Starting from 5-bromo-3-methylpicolinaldehyde,3-methyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)pyridinewas synthesized in analogy to the protocol described for3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)pyridine(Example XX). Diasteromeric mixture of3-methyl-2-(4-methyl-4-((3-(trifluoromethyl)-phenyl)sulfonyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)pyridinewas separated by reverse phase prep HPLC purification to give cis (120mg) and trans diasteromers (560 mg).

cis-isomer (SC-154, SC-155): ¹H NMR (400 MHz, DMSO-d₆): δ 8.76 (s, 1H),8.24 (d, J=7.8 Hz, 1H), 8.11-8.17 (m, 3H), 7.90 (t, J=7.76 Hz, 1H),5.32-5.36 (m, 1H), 4.51 (d, J=9.8 Hz, 1H), 3.73 (d, J=9.84 Hz, 1H), 3.29(s, 3H), 3.19 (t, J=3.08 Hz, 1H), 2.40 (s, 3H), 2.17-2.21 (m, 1H), 1.56(s, 3H).

Two enantiomers of cis isomer was separated by chiral HPLC, using chiralpack 1A column and EtOH/DEA: (100/0.1) as mobile phase to obtain twodesired cis enantiomers (SC-154 and SC-155)

SC-154: (32 mg, off white solid, 1^(st) eluted enantiomer).

SC-155: (25 mg, off white solid, 2^(nd) eluted enantiomer).

trans-isomer (SC-156, SC-157): ¹H NMR (400 MHz, DMSO-d₆): δ 8.84 (s,1H), 8.33 (d, J=7.8 Hz, 1H), 8.22-8.25 (m, 2H), 8.15 (s, 1H), 7.97 (t,J=7.8 Hz, 1H), 5.20 (t, J=7.32 Hz, 1H), 4.42 (d, J=10.28 Hz, 1H), 3.81(d, J=10.24 Hz 1H), 3.29 (s, 3H), 2.95-3.01 (m, 1H), 2.54-2.59 (m, 1H),2.39 (s, 3H), 1.50 (s, 3H).

Two enantiomers of trans isomer was separated by chiral HPLC, usingchiral pack 1C column and Hexane/EtOH/DEA: (80/20/0.1) as mobile phaseto obtain two desired cis enantiomers (SC-156 and SC-157).

SC-156: (213 mg, off white solid, 1^(st) eluted enantiomer).

SC-157: (146 mg, off white solid, 2^(nd) eluted enantiomer).

4-Cyclopropyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-oxazole(Example 32)

Step 1: methyl2-cyclopropyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamido)acetate

To a cold stirring solution of methyl 2-amino-2-cyclopropylacetate(0.072 g, 0.558 mmol, 1 eq) in DMF (4 mL) was addeddiisopropylethylamine (0.29 mL, 1.68 mmol, 3 eq). The RM then stirredfor 10 min at RT. HATU (0.319 g, 0.839 mmol, 1.5 eq) and4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxylicacid (0.2 g, 0.56 mmol, 1 eq) was then added to the RM at 0° C. andfinally the RM stirred for 12 h at RT. The RM was diluted with EtOAc (40mL) and washed with water (5×10 mL) and brine (20 mL). The organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure to getcrude product which was purified by CC to afford pure methyl2-cyclopropyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamido)acetate(0.15 g, 57%) as yellow liquid.

Step 2:2-cyclopropyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamido)aceticacid

To a stirred solution of methyl2-cyclopropyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamido)acetate(0.11 g, 0.237 mmol, 1 eq) in (2:1:1) ratio of THF (4 mL), MeOH (2 mL)and water (2 mL), LiOH (0.024 g, 0.575 mmol, 2.5 eq) was added. The RMwas stirred for 2 h at RT. The reaction was monitored by TLC. The RM wasconcentrated under reduced pressure, diluted with water (20 mL) andwashed with diethylether (2×10 mL). The aq. layer was acidified with 2NHCl solution, and the desired product was extracted with DCM (3×15 mL),dried over anhydr. Na₂SO₄ and concentrated under reduced pressure toafford methyl2-cyclopropyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamido)acetate(0.08 g, 75%) as white solid.

Step 3:N-(1-cyclopropyl-2-(methoxy(methyl)amino)-2-oxoethyl)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide

To a cold stirring solution of N,O-dimethylhydroxylamine hydrochloride(0.126 g, 1.3 mmol, 1.8 eq) in DMF (5 mL) was added DIPEA (0.19 mL, 1.09mmol, 1.5 eq). The RM was then stirred for 10 min at RT. HATU (0.305 g,0.802 mmol, 1.1 eq) and compound 52-cyclopropyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamido)aceticacid (0.33 g, 0.73 mmol, 1 eq) was then added to the RM at 0° C. andfinally the RM was stirred for 12 h at RT. The RM was diluted with EtOAc(40 mL) and washed with water (5×10 mL) and brine (20 mL). The organiclayer was dried over Na₂SO₄ concentrated under reduced pressure to givecrude product which was purified by CC to afford pureN-(1-cyclopropyl-2-(methoxy(methyl)amino)-2-oxoethyl)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide(0.230 g, 64%) as yellow liquid.

Step 4:N-(1-cyclopropyl-2-oxoethyl)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide

To a stirred solution of LAH (0.55 ml, 0.55 mmol, 1 eq) in THF (4 mL),was addedN-(1-cyclopropyl-2-(methoxy(methyl)amino)-2-oxoethyl)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide(0.275 g, 0.55 mmol, 1 eq) at −78° C. The RM was stirred for 20 min at0° C. The reaction was monitored by TLC. After completion the RM wascooled to −78° C., and it was quenched with aq. KHSO₄ solution. The RMwas diluted with EtOAc (40 mL), washed with water (2×10 mL) and brine(10 mL), dried over anhydr. Na₂SO₄ and the solvent was evaporated underreduced pressure to give crudeN-(1-cyclopropyl-2-oxoethyl)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide(0.16 g, 70%) as light yellow liquid.

Step 5:4-cyclopropyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-oxazole

To a stirred solution ofN-(1-cyclopropyl-2-oxoethyl)-4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carboxamide(0.65 g, 1.5 mmol, 1 eq) in toluene (20 mL), POCl₃ (4.5 mL, 4.5 mmol,2.5 eq) was added. The RM was stirred for 12 h at 65° C. Reaction wasmonitored by TLC, the solvent was evaporated and the RM was diluted withEtOAc (70 mL), washed with water (2×20 mL) and brine (20 mL), dried overanhydr. Na₂SO₄ and the solvent was evaporated under reduced pressure togive crude product which was purified by CC to afford pure4-cyclopropyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-oxazole(0.055 g, 9%) as yellow liquid.

SC-158: 1H NMR (400 MHz, DMSO-d₆, δ ppm): 0.73-0.76 (2H), 0.82-0.87(2H), 1.52 (s, 3H), 1.70-1.76 (1H), 1.87-1.90 (1H), 2.25-2.32 (1H),2.39-2.45 (1H), 3.64-3.71 (1H), 4.11-4.15 (1H), 4.55-4.58 (1H), 7.35 (s,1H), 7.72-7.75 (1H), 7.93-7.95 (1H), 8.06-8.08 (1H), 8.13 (s, 1H).

5-Cyclopropyl-3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole(Example 46)

Step 1:4-ethyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-carboxamide

EDC.HCl (2.093 g, 13.66 mmol) and HOBT (1.84 g, 13.66 mmol) were addedto a stirred solution of4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-carboxylicacid (2.5 g, 6.83 mmoL) in THF (50 mL) at 0° C., stirred for 15 min andadded TEA (4.77 mL, 34.15 mmol) followed by NH₄Cl (1.10 g, 20.49 mmol).The resulting mixture was allowed to warm to RT and stirred for 16 h.Reaction mass was diluted with chilled water (40 mL) and extracted withEtOAc (2×100 mL). Combined organic extract was washed with brinesolution (50 mL), dried (Na₂SO₄) and concentrated under reduced pressureto get crude compound. The crude compound was triturated withdiethylether to afford 1.7 g (68%) of4-ethyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-carboxamideas off white solid. The crude was used as such in the next step withoutpurification.

Step 2:4-ethyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-carbonitrile

POCl₃ (0.65 mL, 6.98 mmol) was added to a stirred solution of4-ethyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-carboxamide(1.7, 4.65 mmol) in dry pyridine (3.4 mL) at 70° C. over 10 min. Theresulting mixture was cooled to RT and stirred for 16 h. It was thendiluted with chilled water (30 mL) and extracted with diethylether (3×50mL). Combined organic extract was washed with brine (50 mL), dried(Na₂SO₄) and concentrated under reduced pressure to get crude compound.The crude was triturated with Et₂O to afford 1.1 g (68%) of4-ethyl-4-(3-(trifluoromethyl)-phenyl-sulfonyl)tetrahydro-2H-pyran-2-carbonitrileas a solid.

Step 3:4-ethyl-N-hydroxy-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-carboximidamide

TEA (0.88 mL, 6.34 mmol) and NH₂OH.HCl (0.33 g, 4.75 mmol) were added toa stirred solution of4-ethyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-carbonitrile(1.7, 4.65 mmol) in EtOH (22 mL) at 0° C. The resulting mixture wasstirred at RT for 16 h. The RM was concentrated under reduced pressure.The residue was quenched with chilled water (30 mL) and extracted withDCM (3×50 mL). Combined organic extract was washed with brine (50 mL),dried (Na₂SO₄) and concentrated under reduced pressure to get crudecompound. The crude was triturated with Et₂O to give4-ethyl-N-hydroxy-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-carboximidamide(1.0 g, 83%).

Step 4:4-ethyl-N-hydroxy-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)(hydroxyamino)methyl)cyclopropanecarboxamide

Cyclopropane carbonyl chloride (0.27 g, 2.63 mmol) was added dropwise toa stirred solution of4-ethyl-N-hydroxy-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-carboximidamide(1.0 g, 2.63 mmoL) and TEA (0.73 mL, 5.26 mmoL) in DCM (20 mL) at 0° C.over a period of 10 min. The resulting mixture was s stirred at 0° C.for 2 h, diluted with DCM (50 mL). Combined organic layer was washedwith water (50 mL), brinesolution (50 mL), dried (Na₂SO₄) andconcentrated under reduced pressure to get crude compound. The crude wastriturated with n-pentane to get 1.0 g of4-ethyl-N-hydroxy-4-(3-(trifluoromethyl)phenyl-sulfonyl)tetrahydro-2H-pyran-2-yl)(hydroxyamino)-methyl)-cyclopropanecarboxamideas. The crude was used as such in next step with out purification.

Step 5:5-Cyclopropyl-3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole

CH₃COONa (0.36 g, 4.46 mmol) was added to a solution of4-ethyl-N-hydroxy-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)(hydroxyamino)methyl)cyclopropanecarboxamide(1.0 g, 2.33 mmol) in EtOH (10 mL), water (8 mL) and stirred at 80° C.for 48 h. The reaction mass was concentrated under reduced pressure,quenched with ice water (20 mL) and extracted with DCM (3×20 mL).Combined organic extract was washed with water (30 mL), brine (50 mL),dried (Na₂SO₄) and concentrated under reduced pressure to get crude. Thecrude was purified by CC (0-2% MeOH in CHCl₃) to give 600 mg (63%) of5-Cyclopropyl-3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazoleas a viscous oil.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.23-8.24 (1H), 8.17-8.18 (1H), 8.03(1H), 7.97-7.99 (1H), 4.73-4.75 (1H), 3.93-3.96 (1H), 3.67-3.71 (1H),2.31-2.35 (1H), 2.09-2.14 (1H), 1.91-2.01 (4H), 1.65-1.67 (1H),1.23-1.25 (2H), 1.08-1.09 (2H), 0.97-1.00 (3H).

NOE: C-2 proton & ethyl=cis

Chiral resolution of [cis-rac]5-Cyclopropyl-3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole

[Cis-rac]5-Cyclopropyl-3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazolewas subjected to preparative chiral-SFC (IC-column, MeOH, 90%). Theproducts were dried to give [cis-EN1] SC-238 and [cis-EN2] SC-239.

[cis-EN1] SC-238—analytical chiral SFC: chiralpak IC (250×4.6 mm 5μ), 3g/min, RT, 0.5% DEA in MeOH, 20%, Ret. Time 2.02; ee>95%

[cis-EN2] SC-239—analytical chiral SFC: chiralpak IC (250×4.6 mm 5μ), 3g/min, RT, 0.5% DEA in MeOH, 20%, Ret. Time 2.42; ee>95%

5-[[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-2-(trifluoromethyl)-pyridine(Example 33)

Step 1: 4-Oxo-tetrahydro-pyran-2-carboxylic acid

To a degassed solution of 4-oxo-4H-pyran-2-carboxylic acid (7 g, 50.0mmol) in EtOAc (130 ml) was added palladium carbon (0.700 g, 10% byweight) and the mixture was again degassed thoroughly with Ar andstirred in a paar shaker for 16 hours under hydrogen atmosphere.Reaction was monitored by TLC. The RM was filtered through celite bedand organic portion was concentrated under reduced pressure to obtain,crude 4-Oxo-tetrahydro-pyran-2-carboxylic acid (3.8 g, 52%) as whitesolid. which was used for next step without further purification.

Step 2: 2-Hydroxymethyl-tetrahydro-pyran-4-ol

To a stirred solution of 4-Oxo-tetrahydro-pyran-2-carboxylic acid (3 g,20.54 mmol) in THF (100 ml), Borane dimethyl sulfoxide solution (18.24g, 240 mmol) was slowly added at 0° C. and refluxed for 6 hours at 80°C. Reaction was monitored by TLC, The RM was quenched with water slowlyat 0° C. and filtered through celite bed and organic layer wasconcentrated under reduced pressure to obtain solid. Further this solidwas washed with 30% IPA-CHCl₃ The organic portion was evaporated underreduced pressure to get crude 2-Hydroxymethyl-tetrahydro-pyran-4-ol (2g, 74%) as light brown liquid.

Step 3: 2-(tert-Butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-ol

To a solution of 2-Hydroxymethyl-tetrahydro-pyran-4-ol (7.0 g, 53.03mmol) in DCM (130 ml) was added TEA (8.8 ml, 63.6 mmol) and DMAP (0.258g, 2.1 mmol) followed by tert-butyl silyl chloride (6.3 g, 42.4 mmol) at0° C. Then the RM was stirred at the RT for 12 h. The RM was dilutedwith DCM (200 ml) and washed with water (3×100 ml), brine, dried overanhydr. Na₂SO₄ and concentrated under reduced pressure to give the crudeproduct. The crude was purified by CC by using 25% EA-Hexane as eluentto afford pure2-(tert-Butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-ol (3.5 g,26%) as light yellow liquid.

Step 4: Methanesulfonic acid2-(tert-butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-yl ester

To a solution of2-(tert-Butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-ol (2.6 g g,10.5 mmol) in DCM (50 ml) was added TEA (4.3 ml, 30 mmol) followed bymethane sulphonyl chloride (1.55 ml, 20 mmol) at 0° C. Then the RM wasstirred at the same temperature for 1 h. The RM was diluted with DCM(100 ml) and washed with water (3×50 ml), brine, dried over anhydr.Na₂SO₄ and concentrated under reduced pressure to give the crudeMethanesulfonic acid2-(tert-butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-yl ester(2.8 g, 82%) as yellow liquid, which was used for the next step withoutfurther purification.

Step 5:tert-Butyl-dimethyl-[4-(3-trifluoromethyl-phenylsulfanyl)-tetrahydro-pyran-2-ylmethoxy]-silane

To a stirred solution of Methanesulfonic acid2-(tert-butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-yl ester(3.5 g, 10.8 mmol) in DMF (100 ml), Compound 6(2.8 g, 15.7 mmol), K₂CO₃(2.76 g, 20 mmol) was added and heated to 70° C. for 12 h. Reaction wasmonitored by TLC. The RM was diluted with EtOAc (50 ml), washed withwater (20 ml×2), sat. brine, dried over anhydr. Na₂SO₄, The organicportion was evaporated under reduced pressure to get crude which waspurified by (230-400 mesh silica gel), using 2% EtOAc-hexane as eluentto afford puretert-Butyl-dimethyl-[4-(3-trifluoromethyl-phenylsulfanyl)-tetrahydro-pyran-2-ylmethoxy]-silane(2 g, 46%) as light yellow liquid.

Step 6:tert-Butyl-dimethyl-[4-(3-trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-2-ylmethoxy]-silane

To a stirred solution oftert-Butyl-dimethyl-[4-(3-trifluoromethyl-phenylsulfanyl)-tetrahydro-pyran-2-ylmethoxy]-silane(2.2 g, 5.41 mmol) in (3:1) ratio of MeCN (72 ml), water (24 ml), sodiumperiodate (3.47 g, 16.1 mmol) was added followed by addition ofRuthenium(III)chloride hydrate (0.022 g, 0.106 mmol) at 0° C. Thereaction was continued for 10 min at RT. The reaction was monitored byTLC and it was diluted with EtOAc (100 ml), washed with water (50 ml×2),and brine (50 ml). The organic layer dried over Na2SO4 concentrated inreduced pressure to get the crude material. Crude was purified by CC(100-200 mesh silicagel), using 10% EtOAc/Hexan as eluent to afford puretert-Butyl-dimethyl-[4-(3-trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-2-ylmethoxy]-silane(1.7 g, 73.91%) as off white solid.

Step 7:tert-Butyl-dimethyl-[4-methyl-4-(3-trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-2-ylmethoxy]-silane

To a stirred solution oftert-Butyl-dimethyl-[4-(3-trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-2-ylmethoxy]-silane(2.5 g, 5.70 mmol) in THF (80 ml), NaHMDS (11.4 ml, 11.4 mmol) was addedfollowed by addition of 15-Crown-5 (2.5 g, 11.36 mmol) at −78° C. Thereaction was continued for 20 min. Mel was added and maintained for 45min at −78° C. and finally the RM stirred for 12 hr at RT. The reactionwas monitored by TLC and it was diluted with EtOAc (100 ml), washed withwater (50 ml×2), brine (50 ml) dried over anhydr. Na₂SO₄ and evaporatedunder reduced pressure to give crude which was further purified by CC(silica gel 230-400) using 8% EtOAc/hexane as eluent to affordtert-Butyl-dimethyl-[4-methyl-4-(3-trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-2-ylmethoxy]-silane(1.3 g, 52.0%) as light yellow solid.

Step 8:[4-Methyl-4-(3-trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-2-yl]-methanol

To a cold stirred solution oftert-Butyl-dimethyl-[4-methyl-4-(3-trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-2-ylmethoxy]-silane(0.830 g, 1.8 mmol) in THF (20 ml) TBAF solution (4.5 ml, 4.5 mmol) wasadded. The RM was stirred for 30 min at RT. Reaction was monitored byTLC, solvent was evaporated under reduced pressure to get crudecompound. Crude was purified by CC (silica gel 230-400) using 30%EtOAc/hexane as eluent to afford pure[4-Methyl-4-(3-trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-2-yl]-methanol(0.580 g, 93.5%) as a white solid.

Step 9:5-[4-Methyl-4-(3-trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-2-ylmethoxy]-2-trifluoromethyl-pyridine)

To a stirred solution of[4-Methyl-4-(3-trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-2-yl]methanol(0.3 g, 0.88 mmol) in 10 ml THF was added 6-trifluoromethyl-pyridin-3-ol(0.143 g, 0.88 mmol), PPh₃ (0.345 g, 1.32 mmol) and heated to reflux.Then added DEAD (0.208 ml, 1.32 mmol) and heating continued for 16 h.Then the reaction mass cooled to RT diluted with H₂O and extracted withEtOAc (2×20 ml), washed with brine (15 ml), dried over Na₂SO₄ andconcentrated. The crude was purified by reverse phase prep. HPLC to getpure cis-diastereomer (0.20).

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.43 (1H), 8.23-8.24 (1H), 8.18-8.19(1H), 8.05 (1H), 7.97-7.99 (1H), 7.83-7.84 (1H), 7.60-7.62 (1H),4.15-4.22 (2H), 3.87-3.92 (2H), 3.55-3.60 (1H), 2.00-2.05 (1H),1.90-1.94 (1H), 1.62-1.65 (1H), 1.41-1.44 (4H).

Chiral resolution of [cis racemic]:5-[4-Methyl-4-(3-trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-2-ylmethoxy]-2-trifluoromethyl-pyridine)

[Cis-rac]:5-[4-Methyl-4-(3-trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-2-ylmethoxy]-2-trifluoromethyl-pyridine)was subjected to preparative chiral-HPLC (Chiralpal IA, 0.1% DEA inMeOH, 100 bar, to give [cis-EN1] SC-208 and [cis-EN2] SC-209.

[cis-EN1] SC-208—analytical chiral HPLC: Chiralpak IA (250×4.6 mm 5μ),0.5 mL/min, RT, 0.1% DEA in EtOH 100%, Ret. Time 9.99; ee>95%

[cis-EN2] SC-209—analytical chiral HPLC: Chiralpak IA (250×4.6 mm 5μ),0.5 mL/min, RT, 0.1% DEA in EtOH 100%, Ret. Time 11.85; ee>95%

2-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-[1,3,4]oxadiazole(Example 47)

Step 1:Methyl4-ethyl-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-carboxylate

Conc.sulfuric acid (0.1 mL) was added to a stirred solution of4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-carboxylicacid (1 g, 2.73 mmol) in MeOH (20 mL) at 0° C. and stirred at reflux for4 h. The RM was concentrated under reduced pressure and the residue wasquenched into chilled water (20 ml) and extracted with DCM (3×30 mL).Combined organic extract was washed with aq. NaHCO₃ solution (50 mL) andbrine (50 mL), dried (Na₂SO₄) and concentrated under reduced pressure toget crude. The crude was triturated with n-pentane (10 mL) to afford 800mg of methyl4-ethyl-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-carboxylateas a solid.

Step 2:4-ethyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2carbohydrazide

Hydrazine hydrate (0.286 g, 8.94 mmol, 99% pure) was added to a solutionof the product of step 1 (1.7 g, 4.47 mmoL) in EtOH (34 mL, 20 vol) andstirred at 80° C. for 4 h. The reaction mass was concentrated underreduced pressure and the residue was triturated with Et₂O (20 mL) togive 1.2 g (70%) of4-ethyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazideas an off white solid.

Step 3:4-ethyl-N-(2,2,2-trifluoroacetyl)-4-ethyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide

Trifluoro acetic anhydride (0.53 mL, 3.78 mmol) was added to a stirredsolution of4-ethyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-carbohydrazide(1.2 g, 3.15 mmol), TEA (0.44 mL, 3.15 mmol) in THF (24 mL) and stirredat RT for 16 h. The RM was quenched into ice cold water (20 mL) andextracted with EtOAc (3×20 mL). The combined organic layer was washedwith brine (20 mL), dried (Na₂SO₄) and concentrated under reducedpressure to get crude. The crude was triturated with Et₂O (20 mL) togive 1.1 g (73%) of4-ethyl-N-(2,2,2-trifluoroacetyl)-4-ethyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2carbohydrazideas an off white solid.

Step 4:2-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-[1,3,4]oxadiazole

POCl₃ (0.3 mL, 3.19 mmol) was added to a solution of4-ethyl-N-(2,2,2-trifluoroacetyl)-4-ethyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2carbohydrazide(1.2 g, 3.19 mmoL) in MeCN (24 mL) and stirred at 80° C. for 48 h. Thereaction mass was concentrated under reduced pressure and the residuewas quenched into ice water (50 mL) and extracted with DCM (3×30 mL).The combined organic extract was washed with aq.NaHCO₃ solution (20 mL),water (30 mL), brine solution (50 mL), and dried (Na₂SO₄), concentratedunder reduced pressure to get the crude product. The crude was purifiedby CC (silica gel, 100-200 mesh), 0-0.6% MeOH in CHCl₃ to give 0.9 g.Further purification by prep. TLC (GF254 silica, 3% MeOH in CHCl₃ aseluent) afforded 600 mg of2-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-[1,3,4]oxadiazole(SC-242) as a white solid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.24-8.26 (1H), 8.19-8.21 (1H), 8.06(1H), 7.99-8.01 (1H), 5.08-5.10 (1H), 4.00-4.04 (1H), 3.76-3.80 (1H),2.23-2.28 (1H), 2.16-2.19 (1H), 1.96-2.07 (4H), 1.69-1.72 (1H),0.99-1.01 (3H).

NOE: C-2 proton & ethyl=cis

Chiral resolution of2-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-[1,3,4]oxadiazole(SC-242)

Cis-rac2-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-[1,3,4]-oxadiazolewas subjected to preparative chiral-HPLC (Chiralcel OJ-H column, hexane:EtOH, 75:25) to give cis-EN1 SC-240 and cis-EN2 SC-241.

[cis-EN1] SC-240—analytical chiral HPLC: Chiralpak OJ-H (250×4.6 mm 5μ),0.2% DEA in hexane: MeOH, 75:25, 1 mL/min, Ret. Time 7.55; ee>95%

[cis-EN2] SC-241—analytical chiral HPLC: Chiralpak OJ-H (250×4.6 mm 5μ),0.2% DEA in hexane: MeOH, 75:25, 1 mL/min, Ret. Time 9.88; ee>95%

5-Chloro-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 48)

Step 1: 2-(5-chloropyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

Methanesulfonic acid (20.3 g, 212.0 mmol) was added to a solution of5-chloropicolinaldehyde (3 g, 21.20 mmol) and 3-buten-1-ol (2.2 g, 31.80mmol) in DCM (30 mL) at 0° C., stirred for 3 h at 0° C.-15° C. The RMwas quenched into ice water, diluted with DCM (15 mL) and washedsequentially with sat. aq. NaHCO₃ solution (2×50 mL), water (100 mL),brine (100 mL), dried (anhydr. Na₂SO₄) and concentrated under reducedpressure to get crude 2-(5-chloropyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (6.2 g crude) as a brown oil. This was taken to thenext step without further purification.

Step 2:5-chloro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

3-(Trifluoromethyl)benzene thiol (7.6 g, 42.61 mmol) was added to asuspension of K₂CO₃ (6 g, 42.61 mmol),2-(5-chloropyridin-2-yl)tetrahydro-2H-pyran-4-yl methanesulfonate (6.2g, 21.30 mmol) in DMF (50 mL) and the RM was heated at 60° C. for 5 hand stirred for 14 h at RT. After completion of reaction, the mixturewas diluted with water (100 mL) and extracted with EtOAc (50 mL×3). Theorganic extract was washed with water (100 mL), brine (100 mL), dried(anhydr. Na₂SO₄) and concentrated under reduced pressure to get crudecompound. The crude compound was purified by CC (silica gel 60-120 mesh,0-10% EtOAc in PE) to obtain 5.5 g (70%) of5-chloro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridineas thick oily liquid.

Step 3:5-chloro-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

5-chloro-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(5.5 g, 14.74 mol) was dissolved in EtOH (110 mL) and a solution ofoxone (27 g, 44.23 mmol) in water (55 mL) was added. The total reactionmass was stirred at RT for 16 h. The RM was diluted with water (100 mL)and extracted with DCM (3×50 mL). The combined organic extract waswashed with brine (100 mL), dried (anhydr. Na₂SO₄) and concentrated toget crude. The crude compound was purified by CC (silica gel 60-120mesh, 0-30% EtOAc in PE) to obtain5-chloro-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(2 g, 51%) as a solid.

Step 4:5-Chloro-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

A solution of5-chloro-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(2 g, 4.93 mmol) in THF (20 mL) was cooled to −78° C. and t-BuOK (1 Msolution in THF; 10 mL, 9.87 mmol) was added drop-wise, stirred for 30min at same temperature. Mel (0.65 mL, 9.87 mmol) was added and theresulting mixture was warmed to RT and stirred for 16 h. The reactionmass was diluted with water (50 mL), EtOAc (50 mL). The combined organiclayer was washed with water (100 mL) and brine (100 mL), dried (anhydr.Na₂SO₄) and concentrated under reduced pressure to get crude compound.The crude compound was purified by CC (silica gel 60-120 mesh, 0-35%EtOAc in PE) to obtain 1.1 g of5-chloro-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineas an off white solid. The compound was further purified by preparativeHPLC (Kromosil C17, 250×25 mm, 5 m, 70% MeOH).

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.55 (1H), 8.20-8.22 (1H), 8.15-8.17(1H), 8.04 (1H), 7.93-7.97 (2H), 7.46-7.48 (1H), 4.61-4.64 (1H),4.07-4.10 (1H), 3.72-3.77 (1H), 2.11-2.16 (1H), 1.93-1.97 (1H),1.85-1.88 (1H), 1.47-1.50 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of5-Chloro-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

Cis-rac5-Chloro-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to preparative chiral-SFC (Chiralpak AD-H, 20% MeOH) togive cis-EN1 SC-243 and cis-EN2 SC-244.

[cis-EN1] SC-243—analytical chiral SFC: Chiralpak AD-H (250×4.6 mm 5μ),0.5% DEA in MeOH 30%, 3 g/min, Ret. Time 2.62; ee>95%.

[cis-EN2] SC-244—analytical chiral SFC: Chiralpak AD-H (250×4.6 mm 5μ),0.5% DEA in MeOH 30%, 3 g/min, Ret. Time 3.07; ee>95%.

Synthesis of Heteroaryl-Aldehydes 4,6-dimethoxynicotinaldehyde

Step 1: 4,6-dimethoxynicotinic acid

Sodium (8.23 g, 358.20 mmol) was added to dry MeOH (180 mL) at RT, thenmethyl 4,6-dichloronicotinate (9.0 g, 44.77 mmol) was added at RT. Thereaction was heated at reflux for 18 h and subsequently concentrated invacuo. The residue was diluted with water (50 mL) and acidified with aqHCl solution up to pH-2.0. A solid precipitated. The solid was filteredand washed with water and dried in vacuo for 2 h to get4,6-dimethoxynicotinic acid (6.5 g, 80%) as a white solid.

Step 2: Methyl 4,6-dimethoxynicotinate

Dimethylsulfate (5.0 mL, 53.27 mmol) was added to a suspension of4,6-dimethoxynicotinic acid (6.5 g, 35.51 mmol) and K₂CO₃ (7.35 mmol,35.51) in DMF (100 mL) at RT and then stirred for 5 h. After completionof the reaction, the mixture was diluted with water (250 mL) andextracted with EtOAc (250 mL×3). The organic extract was washed withwater (300 mL), brine (200 mL), dried (Na₂SO₄) and concentrated underreduced pressure to get methyl 4,6-dimethoxynicotinate (6.0 g, 86%) as awhite solid.

Step 3: (4,6-dimethoxypyidin-3-yl) methanol

A solution of methyl 4,6-dimethoxynicotinate (6.0 g, 30.45 mmol) in THF(30 mL) was added to a suspension of LiAlH₄ (1.73 g, 45.68 mmol) in THF(60 mL) at 0° C. The total reaction mass was stirred at 0° C. for 2 h.After completion of reaction, the RM was quenched with sat. Na₂SO₄ at 0°C., then diluted with EtOAc (150 mL) and filtered through celite pad,then reaction mass was extracted with EtOAc (150 mL×2). The organicextract was washed with water (300 mL), brine (200 mL), dried Na₂SO₄ andconcentrated under reduced pressure to get (4,6-dimethoxypyidin-3-yl)methanol (4.8 g, 94%) as a white solid.

Step 4: 4,6-dimethoxynicotinaldehyde

DMP (18.1 g, 42.85 mmol) was added to a clear solution of(4,6-dimethoxypyidin-3-yl) methanol (4.8 g, 28.57 mmol) in DCM (100 mL)at 0° C. The total RM was slowly warmed to RT and stirred for 12 h. TheRM was filtered through celite and washed with DCM. The total organiclayer was washed with water (100 mL) followed by sat. NaHCO₃ solution(100 mL) and brine, dried over Na₂SO₄. Concentrated under reducedpressure to get 4,6-dimethoxynicotinaldehyde (4.0 g, 85%) as a whitesolid.

6-methoxy-4-methylnicotinaldehyde

Step 1: 5-bromo-2-methoxy-4-methylpyridine

Sodium acetate (3.54 g, 43.23 mmol) was added to a solution of2-methoxy-4-methylpyridine 54-5-1 (5.0 g, 39 mmol) in EtOAc (25 mL). Br₂(1.52 mL, 58 mmol) was added drop wise over 20 min at 0° C. The RM wasstirred at 50° C. for 18 h. The total reaction mass was cooled and afterdiluting with water, the pH was adjusted to 8 with aq. NaOH. The organiclayer was separated and aq. layer extracted with EtOAc (250 mL×3). Thecombined extract was washed with water (300 mL), brine (200 mL), dried(Na₂SO₄) and concentrated under reduced pressure to get crude compound.The crude compound was purified by CC (silica gel 100-200 mesh, 0-5%EtOAc in PE) to obtain 5-bromo-2-methoxy-4-methylpyridine (2.82 g, 40%)as liquid.

Step 2: 6-methoxy-4-methylnicotinaldehyde

A solution of BuLi (1.6 M in Hexane; 15.6 mL, 25 mmol) was added to5-bromo-2-methoxy-4-methylpyridine (4.6 g, 22.77 mmol) in dry THF (60mL) under Ar at −75° C. for 20 min. The RM was stirred at −75° C. for 1h and then anhydr. DMF (2.5 mL, 34 mmol) was added slowly. The RM waswarmed to RT and stirred for 12 h. The RM was quenched with sat. NH₄Cland was extracted with DCM. The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to get6-methoxy-4-methylnicotinaldehyde (4.0 g, 85%) as a white solid.

5-fluoro-6-methoxynicotinaldehyde

Step 1: 5-Bromo-3-fluoro-2-methoxypyridine

To a solution of 3-fluoro-2-methoxypyridine (20 g, 157.48 mmol), sodiumacetate (25.74 g, 314.0 mmol) in AcOH (60 mL) was added dropwise asolution of Br₂ (20.32 mL, 393.70 mmol) in AcOH (40 mL) at 10° C. andthe RM stirred at RT for 16 h. The RM was quenched into ice water (200mL) and then basified with 6N NaOH solution to pH 9 and filtered thesolid. The solid was dissolved in Et₂O (300 mL), washed with brine,dried (Na₂SO₄), filtered, concentrated under reduced pressure to give5-bromo-3-fluoro-2-methoxypyridine (20 g, 61%) as white solid

Step 2: Methyl 5-fluoro-6-methoxynicotinate

TEA (10.21 mL, 72.81 mmol) was added to a mixture of 54-9-2 (5 g, 24.27mmol), BINAP (1.51 g, 2.42 mmol) and Pd (dppf) Cl₂ DCM complex (1.98 g,2.42 mmol) in MeOH (100 mL) in a steel bomb. The steel bomb was filledwith CO gas (120 psi) and stirred at 120° C. for 20 h. The reaction masswas cooled to RT, excess gas evacuated in vacuo and filtered through acelite bed, and washed with EtOAc. The filtrate was concentrated underreduced pressure. The residue was purified by CC (0-5% EtOAc in PE) togive methyl 5-fluoro-6-methoxynicotinate (2 g, 44.5%) as a white solid.

Step 3: (5-fluoro-6-methoxypyridin-3-yl) methanol

LiAlH4 (1.64 g, 43.24 mmol) was added portion wise to a stirred solutionof methyl 5-fluoro-6-methoxynicotinate (8 g, 43.24 mmol) in dry THF (160mL) at −20° C. and stirred for 2 h at −20° C. to −15° C. The RM wasslowly quenched with sat. Na₂SO₄ solution (100 mL). The precipitatedsalts were filtered through celite bed and the cake was washed withEtOAc (3×50 mL). The filtrate was concentrated under reduced pressure togive crude (5-fluoro-6-methoxypyridin-3-yl) methanol (6.8 g, crude) as aliquid.

Step 4: 5-fluoro-6-methoxynicotinaldehyde

DMP (27.37 g, 64.41 mmol) was added portion wise to a stirred solutionof (5-fluoro-6-methoxypyridin-3-yl)methanol (6.8 g, 43.83 mmol) in DCM(150 mL) at 0° C. and stirred for 16 h at RT. The RM was filteredthrough celite and washed with DCM (3×50 mL). The filtrate was washedwith aq. NaHCO₃ (200 mL), water (100 mL), brine (150 mL), dried(Na₂SO₄), filtered, concentrated under reduced pressure to give crude.The crude was purified by CC (silica-gel 60-120 mesh, 0-15% EtOAc in PE)to give 5-fluoro-6-methoxynicotinaldehyde (6.0 g, 89%) as a white solid.

4-fluoro-6-methoxynicotinaldehyde

Step 1: 5-bromo-4-fluoro-2-methoxypyridine

Sodium acetate (3.54 g, 43.23 mmol), EtOAc (25 mL) and2-methoxy-4-fluoropyridine (5.0 g) were mixed in a round bottom flask.Br₂ (1.52 mL, 0.058 mol) was added drop wise to this solution over 20min at 0° C. The RM was stirred at 50° C. for 18 h. The total RM wascooled and water was added to RM. Aq. NaOH was added drop wise to pH-8.The organic layer was separated and the aq. layer extracted with EtOAc(250 mL×3). The organic extract was washed with water (300 mL), brine(200 mL), dried (Na₂SO₄) and concentrated under reduced pressure to getthe crude compound. The crude compound was purified by CC (0-5% EtOAc inPE) to obtain the desired product (2.82 g, 35%) as a liquid.

Step 2: methyl 4-fluoro-6-methoxynicotinate

TEA (17.9 mL, 0.1323 mol) was added to a mixture of5-bromo-4-fluoro-2-methoxypyridine (8 g, 0.044 mol), BINAP (2.74 g, 4.41mmol) and Dichloro(1,1′-bis(dppf)palladium(II) DCM complex (3.60 g, 4.41mmol) in MeOH (100 mL) in a steel bomb, charged with CO gas (120 psi)and heated at 120° C. for 20 h. The reaction mass was cooled to RT,excess gas evacuated in vacuo and filtered over celite. The filtrate wasconcentrated under reduced pressure. The residue upon purification by CC(0-5% EtOAc in PE) gave methyl 4-fluoro-6-methoxynicotinate (4.08 g,56%) as a white solid.

Step 3: (4-fluoro-6-methoxypyridin-3-yl)methanol

LiAlH₄ (0.985 g, 25.9 mmol) was added portion wise to a stirred solutionof methyl 4-fluoro-6-methoxynicotinate (4 g, 43.24 mmol) in dry THF (60mL) at −20° C. and stirred for 2 h at −20° C. to −15° C. The RM wasslowly quenched with sat. Na₂SO₄ solution (50 mL). The precipitatedsalts were filtered through celite and cake was washed with EtOAc (3×250mL). The filtrate was concentrated under reduced pressure to give crude(4-fluoro-6-methoxypyridin-3-yl)methanol (3.0 g, crude, 88%) as aliquid.

Step 4: 4-fluoro-6-methoxynicotinaldehyde

DMP (12.1 g, 28.32 mmol) was added portion wise to a stirred solution of(4-fluoro-6-methoxypyridin-3-yl)methanol (3 g, 19.10 mmol) in DCM (50mL) at 0° C. and stirred for 16 h at RT. The RM was filtered throughcelite and washed with DCM (3×50 mL). The filtrate was washed withaq.NaHCO₃ (200 mL), water (100 mL), brine (150 mL), dried (Na₂SO₄),filtered, concentrated under reduced pressure to give the crude reactionproduct. The crude product was purified by CC (0-15% EtOAc in PE) togive 4-fluoro-6-methoxynicotinaldehyde (1.6 g, 55%) as a white solid.

4-fluoro-6-methoxynicotinaldehyde

Step 1: (5-bromo-3-chloropyridin-2-yl)methanol

NaBH₄ (18.24 g, 480.0 mmol) was added portion wise to a stirred solutionof methyl 5-bromo-3-chloropicolinate (20 g, 80.0 mmol) in dry THF (200mL) and MeOH (200 ml) at 0° C. and stirred for 6 h at RT. The RM wasslowly quenched with water (500 mL) and extracted with EtOAc (3×200 mL).The organic layer was washed with brine (300 mL), then dried (Na₂SO₄),filtered and evaporated the solvent in vacuo to give(5-bromo-3-chloropyridin-2-yl)methanol (16 g, crude), as a thick liquid.The crude was taken into next step.

Step 2: 5-bromo-3-chloropicolinaldehyde

DMP (45.83 g, 102.10 mmol) was added portion wise to a stirred solutionof (5-bromo-3-chloropyridin-2-yl)methanol (16 g, 72.07 mmol) in DCM (320mL) at 0° C. and stirred for 16 h at RT. The RM was filtered throughcelite and washed with DCM (3×100 mL). The filtrate was washed withAq.NaHCO₃ (200 mL), water (200 mL), brine (250 mL), dried (Na₂SO₄),filtered, concentrated under reduced pressure to give crude. The crudewas purified by CC (0-5% EtOAc in PE) to give5-bromo-3-chloropicolinaldehyde (10 g, 66%) as light yellow solid.

3-chloro-5-(trifluoromethyl)picolinaldehyde

Step 1: ethyl 3-chloro-5-(trifluoromethyl)picolinate

Sodium acetate (15.3 g, 186.9 mmol) was added to a mixture of2,3-dichloro-5-(trifluoromethyl)pyridine (40 g, 186.9 mmol), Pd(OAc)₂(5.4 g, 24.2 mmol) and Pd(dppf)Cl₂ DCM complex (13.4 g, 24.2 mmol) inEtOH (400 mL) in an autoclave. The autoclave was filled with CO gas (220psi) and stirred at 90° C. for 6 h. The reaction mass was cooled to RT,excess gas evacuated in vacuo and the reaction mass was filtered througha celite bed. It was washed with EtOAc and the clear filtrate wasconcentrated under reduced pressure. The residue was purified by CC(0-5% EtOAc in PE) and the pure fractions were concentrated at below 40°C. to get ethyl 3-chloro-5-(trifluoromethyl)picolinate (40 g, 85%) as awhite solid.

Step 2: (3-chloro-5-(trifluoromethyl)pyridin-2-yl)methanol

NaBH₄ (12 g, 31.6 mmol) was added portion wise to a stirred solution ofethyl 3-chloro-5-(trifluoromethyl)picolinate (40 g, 15.8 mmol) in MeOH(200 ml) at 0° C. and stirred for 4 h at RT. The RM was slowly quenchedwith water (500 mL) and the organic product was extracted with EtOAc(3×200 mL). The organic layer was washed with brine (300 mL), then driedover anhydr. Na₂SO₄, filtered and evaporated the solvent under vacuo togive crude product. The crude was purified by CC (0-15% EtOAc in PE) andthe pure fractions were concentrated at below 40° C. to give(3-chloro-5-(trifluoromethyl)pyridin-2-yl)methanol (20 g, 60%), as athick liquid.

Step 3: (3-chloro-5-(trifluoromethyl)pyridin-2-yl)methanol

DMP (60.2 g, 142.10 mmol) was added portion wise to a stirred solutionof (3-chloro-5-(trifluoromethyl)pyridin-2-yl)methanol (15 g, 71.0 mmol)in DCM (100 mL) at 0° C. and stirred for 3 h at RT. The RM was filteredthrough a celite bed and washed with DCM (3×100 mL). The clear filtratewas washed with aq. NaHCO₃ (200 mL), water (200 mL), brine (250 mL),dried over anhydr. Na₂SO₄, filtered, concentrated under reduced pressureto get the crude product. The crude was purified by CC (0-5% EtOAc inPE) to give (3-chloro-5-(trifluoromethyl)pyridin-2-yl)methanol (8 g,57%) as liquid.

5-bromo-3-(trifluoromethyl) picolinaldehyde

Step 1: 5-bromo-3-(trifluoromethyl)pyridin-2-amine

N-bromosuccinimide (20.83 g, 117.28 mmol) was portion wise added to astirred solution of 3-(trifluoromethyl)pyridin-2-amine (19 g, 117.28mmol) in MeCN (380 mL) at 0° C. The RM was stirred for 4 h at RT. The RMwas quenched with aq. NaHCO₃ solution (pH-8) and then filtered. Thesolid was washed with water (200 mL), and the product was dissolved withEtOAc (300 mL). The organic layer was dried over anhydr. Na₂SO₄,filtered and solvent was concentrated under reduced pressure to give5-bromo-3-(trifluoromethyl)pyridin-2-amine (25 g, 88%) as a solid.

Step 2: 2,5-dibromo-3-(trifluoromethyl)pyridine

Br₂ (8.60 mL, 166.6 mmol) was added drop wise to a stirred solution of5-bromo-3-(trifluoromethyl)pyridin-2-amine (25 g, 104.1 mmol) and 47%HBr in water (100 mL) at −15° C. To the RM was added aq. sodium nitritesolution (19.4 g, 281.24 mmol in 50 mL of water) drop wise at the sametemperature for 3 h. The RM was stirred for 4 h at RT. The RM was cooledto −15° C. and basified with 3N KOH solution (pH-9) and then filtered.The solid was washed with water (300 mL) and solid was dissolved intoDCM (300 mL). The organic layer was dried over anhydr. Na₂SO₄, filteredand solvent was concentrated under reduced pressure to give2,5-dibromo-3-(trifluoromethyl)pyridine (20 g, 63%) as a solid.

Step 3: 5-bromo-3-(trifluoromethyl) picolinaldehyde

1.6M nBuLi in hexane (4.1 mL, 6.57 mmol) was added drop wise to astirred solution of 2,5-dibromo-3-(trifluoromethyl)pyridine (18 g, 29.60mmol) in DCM (180 mL) at −78° C. The RM was stirred at same temperaturefor 20 min. To the RM was added N-formylmorpholine (5.38 mL, 53.28 mmol)drop wise at −78° C. The RM was stirred for 1 h at −78° C. The RM wasquenched with aq. NH₄Cl solution at −78° C. and the organic compound wasextracted with DCM (3×100 mL); the organic layer was washed with brineand dried over anhydr. Na₂O₄, filtered and solvent was concentratedunder reduced pressure to give 5-bromo-3-(trifluoromethyl)picolinaldehyde (7.5 g, 50%) as a solid.

5-bromo-3-(trifluoromethyl) picolinaldehyde

Step 1: 5-bromo-3-methoxypicolinonitrile

To a stirred solution of 5-bromo-2-cyano-3-nitropyridene (5 g, 0.021mol) in MeOH (50 mL) at 0° C. was added 0.5M sodium methoxide (40 mL)and the RM was heated to reflux and stirred for 8 hr. After reactioncompletion the mixture was concentrated under reduced pressure to givecrude 5-bromo-3-methoxypicolinonitrile. The crude was purified by CC(0-15% EtOAc in PE) and concentrated at below 45° C. to give5-bromo-3-methoxypicolinonitrile (3.4 g, 70%), as a solid.

Step 2: 5-bromo-3-methoxypicolinic acid hydrochloride

5-Bromo-3-methoxypicolinonitrile (7 g, 0.033 mol) was dissolved in 12NHCl (10 mL) at 0° C. The RM was heated to reflux and stirred for 8 hr.After reaction completion the RM was concentrated under reduced pressureto give crude 5-bromo-3-methoxypicolinic acid hydrochloride which isdirectly used for the next step. (7.8 g, 97%), as a solid.

Step 3: methyl 5-bromo-3-methoxypicolinate

5-Bromo-3-methoxypicolinic acid hydrochloride (8 g, 0.034 mol) wasdissolved in MeOH (80 mL) cooled to 0° C. then charged thionyl chloride(24 mL 0.347 mol). The RM heated to reflux and stirred for 8 h. Afterreaction completion the RM was concentrated under reduced pressure. TheRM was poured on ice-water and neutralized with sodium bicarbonate andextracted with EtOAc (3×200 mL). The organic layer was washed with brine(300 mL), then dried (Na₂SO₄), filtered and evaporated the solvent undervacuo to give crude methyl 5-bromo-3-methoxypicolinate. The residue waspurified by CC (0-15% EtOAc in PE) and concentrated at below 45° C. togive methyl 5-bromo-3-methoxypicolinate (6 g, 81%), as a thick liquid.

Step 4: (5-bromo-3-methoxypyridin-2-yl)methanol

NaBH₄ (3.26 g, 0.085 mol) was added portion wise to a stirred solutionof methyl 5-bromo-3-methoxypicolinate 61-19-4 (7 g, 0.028 mol) in EtOH(100 mL) at 0° C. and stirred for 4 h at RT. The RM was slowly quenchedwith water (500 mL) and extracted with EtOAc (3×200 mL). The organiclayer was washed with brine (300 mL), then dried (Na₂SO₄), filtered andevaporated the solvent under vacuo to give crude(5-bromo-3-methoxypyridin-2-yl)methanol. The residue was purified by CC(0-15% EtOAc in PE) and concentrated at below 40° C. to give(5-bromo-3-methoxypyridin-2-yl)methanol (5.8 g, 92%), as a thick liquid.

Step 5: 5-bromo-3-methoxypicolinaldehyde

DMP (14.5 g, 0.034 mol) was added portion wise to a stirred solution of61-19-5 (5 g, 0.022 mol) in DCM (50 mL) at 0° C. and stirred for 3 h atRT. The RM was filtered through celite and washed with DCM (3×100 mL).The filtrate was washed with aq. NaHCO₃ (100 mL), water (100 mL), brine(150 mL), dried (Na₂SO₄), filtered, concentrated under reduced pressureto give crude. The crude was purified by CC (0-5% EtOAc in PE) to give2,5-dibromo-3-(trifluoromethyl)pyridine (2.6 g, 53%) as solid.

3-bromo-5-chloropicolinaldehyde

Step 1: 3-bromo-5-chloropicolinaldehyde

n-Buli (46.0 ml, 73.71 mmol) was added drop wise to a stirred solutionof 2,3-dibromo-5-chloropyridine (20 g, 73.71 mmol) in DCM (200 ml) at−78° C. and stirred for 30 min. To the RM was added DMF (6.9 ml, 88.45mmol) at −78° C. and stirred for 30 min. The RM was slowly quenched withsat. aq. NH₄Cl solution (100 mL) and the organic product was extractedwith EtOAc (3×100 mL). The organic layer was washed with brine (200 mL),then dried over anhydr. Na₂SO₄, filtered and evaporated the solvent invacuo to get crude product. The crude product was purified by CC (0-5%EtOAc in PE) to get 3-bromo-5-chloropicolinaldehyde (3.4 g, 26%) as athick liquid.

3-chloro-5-(difluoromethoxy)picolinaldehyde

Step 1: ethyl 3-chloro-5-hydroxypicolinate

Sodium acetate (4.0 g, 49.38 mmol) was added to a mixture of5,6-dichloropyridin-3-ol (8 g, 49.38 mmol), Pd(OAc)₂ (1.43 g, 6.41 mmol)and Pd(dppf)Cl₂ DCM complex (5.23 g, 6.41 mmol) in EtOH (100 mL) in anautoclave. The autoclave was filled with CO gas (220 psi) and stirred at90° C. for 6 h. The reaction mass was cooled to RT, excess gas evacuatedin vacuo and the reaction mass was filtered through a celite bed. It waswashed with EtOAc and the clear filtrate was concentrated under reducedpressure. The residue was purified by CC (0-40% EtOAc in PE) and thepure fractions were concentrated to get ethyl3-chloro-5-hydroxypicolinate (9.2 g, 93%) as a white solid.

Step 2: ethyl 3-chloro-5-(difluoromethoxy)picolinate

To stirred solution of ethyl 3-chloro-5-hydroxypicolinate (9.2 g, 45.77mmol) in dry DMF (100 mL) was added K₂CO₃ (18.9 g, 137.31 mmol) at RT.The RM was heated to 90° C. and purged with Freon gas for 2 h. The RMwas diluted with water (250 mL) and the organic product was extractedwith EtOAc (250 mL×2). The organic extract was washed with water (2×150mL), brine (100 mL), dried (anhydr. Na₂SO₄) and concentrated underreduced pressure to get compound ethyl3-chloro-5-(difluoro-methoxy)picolinate (9.0 g, crude) as a yellowliquid. The crude was taken as such for the next step.

Step 3: (3-chloro-5-(difluoromethoxy)pyridin-2-yl)methanol

NaBH₄ (5.42 g, 143.43 mmol) was added portion wise to a stirred solutionof ethyl 3-chloro-5-(difluoromethoxy)picolinate (9.0 g, 35.85 mmol) inMeOH (100 ml) at 0° C. and stirred for 4 h at RT. The RM was slowlyquenched with water (200 mL) and the organic product was extracted withEtOAc (3×200 mL). The organic layer was washed with brine (300 mL), thendried over anhydr. Na₂SO₄, filtered and evaporated the solvent undervacuo to give crude product. The crude was purified by CC (0-15% EtOAcin PE) and the pure fractions were concentrated at below 40° C. to give(3-chloro-5-(difluoro-methoxy)pyridin-2-yl)methanol (7.0 g, 92% (for twosteps), as a thick liquid.

Step 4: 3-chloro-5-(difluoromethoxy)picolinaldehyde

DMP (21.6 g, 50.97 mmol) was added portion wise to a stirred solution of(3-chloro-5-(difluoromethoxy)pyridin-2-yl)methanol (7.0 g, 33.98 mmol)in DCM (100 mL) at 0° C. and stirred for 16 h at RT. The RM was filteredthrough a celite bed and washed with DCM (3×100 mL). The clear filtratewas washed with aq. NaHCO₃ (200 mL), water (200 mL), brine (250 mL),dried over anhydr. Na₂SO₄, filtered, concentrated under reduced pressureto get the crude product. The crude was purified by CC (0-5% EtOAc inPE) to give 3-chloro-5-(difluoromethoxy)picolinaldehyde (5.8 g, 85%) asliquid.

3-chloro-5-(difluoromethyl)picolinaldehyde

Step 1: 5,6-dichloro-N-methoxy-N-methylnicotinamide

EDC.HCl (24.92 g, 130.2 mmol), HOBt (17.95 g, 130.2 mmol) were addedsequentially to a stirred solution of 5,6-dichloro nicotinic acid (12.5g, 130.2 mmol), TEA (27 mL, 130.2 mmol) in DCM (250 mL) at 0° C. andstirred for 30 min at same temperature. To the RM was addedN,O-dimethylhydroxylamine.HCl (12.7 g, 130.2 mmol) and slowly warmed toRT. The RM was stirred for 17 h at RT and quenched with water (100 mL),the organic product was extracted with DCM (2×50 mL). The organic layerwas washed with brine (2×50 mL), then dried (anhydr. Na₂SO₄), filteredand evaporated the solvent under vacuo to give5,6-dichloro-N-methoxy-N-methylnicotinamide (9.3 g, 60%) as a thickliquid

Step 2: 5,6-dichloronicotinaldehyde

A 2M solution of LiAlH₄ in THF (19.2 mL, 38.29 mmol) was added to asolution of 5,6-dichloro-N-methoxy-N-methylnicotinamide (22 g, 76.59mol) in THF (360 mL) at −78° C. and stirred for 30 min at sametemperature. The RM was quenched with sat. Na2SO4 solution and filteredthe salts through celite bed, washed with EtOAc. The filtrate was dried(anhydr. Na₂SO₄), filtered and evaporated the solvent under vacuo togive crude as a thick liquid. The crude was purified by CC (0-5% EtOAcin PE) to give 12 g (75%) of 5,6-dichloronicotinaldehyde as liquid.

Step 3: 2,3-dichloro-5-(difluoromethyl)pyridine

DAST (32.8 mL, 38.29 mmol) was added to a solution of5,6-dichloronicotinaldehyde (11 g, 62.59 mol) in DCM (110 mL) at −78° C.and stirred for 30 min and slowly warmed to RT and stirred for 17 h. TheRM was quenched carefully with sat. NaHCO₃ solution and the organicproduct was extracted with EtOAc. The organic layer was washed withbrine (2×100 mL), then dried (anhydr. Na₂SO₄), filtered and evaporatedthe solvent under vacuo to give crude, which was purified by CC (0-10%EtOAc in PE) to give 10 g (81%) of2,3-dichloro-5-(difluoromethyl)pyridine.

Step 4: ethyl 3-chloro-5-(difluoromethyl) picolinate

CH₃COONa (4.2 g, 51.10 mmol) was added to a mixture of2,3-dichloro-5-(difluoromethyl)pyridine (10 g, 51.10 mmol), Pd(OAc)₂(1.5 g, 6.6 mmol) and PdCl₂(dppf) DCM complex (3.6 g, 6.6 mmol) in EtOH(100 mL) in a steel bomb, charged with CO gas (220 psi) and heated at90° C. for 6-8 h. The reaction mass was cooled to RT, excess gas wasevacuated in vacuo and RM was concentrated under reduced pressure. Theresidue was purified by CC (0-10% EtOAc in PE) to get 10 g (80%) ofethyl 3-chloro-5-(difluoromethyl) picolinate as a thick liquid.

Step 5: (3-chloro-5-(difluoromethyl)pyridin-2-yl)methanol

NaBH₄ (2.41 g, 63.90 mmol) was slowly added to a solution of ethyl3-chloro-5-(difluoromethyl)-picolinate (10 g, 42.6 mmol) at 0° C. andslowly warmed to RT and stirred for 4 h. The RM was evaporated and theresidue was quenched with water (200 mL) and the organic product wasextracted with EtOAc (2×100 mL). The organic layer was washed with brine(2×100 mL), then dried (anhydr. Na₂SO₄), filtered and evaporated thesolvent under vacuo to give 7 g (86%) of(3-chloro-5-(difluoromethyl)pyridin-2-yl)methanol as a thick liquid.

Step 6: 3-chloro-5-(difluoromethyl)picolinaldehyde

DMP (7 g, 72.60 mmol) was slowly added to a solution of(3-chloro-5-(difluoromethyl)pyridin-2-yl)methanol (7 g, 36.30 mmol) at0° C. and slowly warmed to RT and stirred for 17 h. The RM was filteredthrough celite bed and washed with DCM. The filtrate was sat. NaHCO₃(2×100 mL), brine (2×100 mL), then dried (anhydr. Na₂SO₄), filtered andevaporated the solvent under vacuo to give crude. The crude was purifiedby CC (60-10% EtOAc in PE) to get 7 g (86%) of3-chloro-5-(difluoromethyl)picolinaldehyde as oil.

The following compounds (examples 49-55) were prepared from thealdehydes described above or from commercially available aldehydes orfrom intermediates described within this application in analogy to5-chloro-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(example 48)

2,4-Dimethoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 49)

A solution of2,4-dimethoxy-5-(4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(1.8 g, 4.176 mmol) in THF (40 mL) was cooled to −78° C. and t-BuOK (1 Msolution in THF (8.5 mL, 8.35 mmol) was added drop-wise. The totalreaction mass was stirred at −78° C. for 30 min, then Mel (0.7 mL, 10.44mmol) was added and the resulting mixture was warmed to RT and stirredfor 16 h. The reaction mass was diluted with EtOAc (150 mL) and washedwith water (50 mL) and brine (100 mL), dried (Na₂SO₄) and concentratedunder reduced pressure to get crude compound. The crude compound waspurified by column (0-20% EtOAc in PE to obtain2,4-Dimethoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(1.1 g, 61% LCMS 90%&8%). The isomers were separated by prep HPLC(reverse phase) to get cis (0.7 g, 39%) and Trans (30 mg) as a whitesolids

trans-rac2,4-Dimethoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-247

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.22-8.23 (2H), 8.08 (1H), 8.00-8.02(1H), 7.97 (1H), 6.4 (1H), 5.25-5.27 (1H), 4.11-4.15 (1H), 3.97-4.00(1H), 3.92 (3H), 3.82 (3H), 2.29-2.31 (1H), 2.16-2.19 (1H), 1.85-1.90(1H), 1.55-1.59 (1H), 1.14 (3H).

Cis-rac2,4-Dimethoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.20-8.22 (1H), 8.17-8.18 (1H), 8.05(1H), 7.94-7.97 (1H), 7.91 (1H), 6.37 (1H), 4.63-4.66 (1H), 4.01-4.04(1H), 3.82 (3H), 3.77 (3H), 3.65-3.70 (1H), 2.07-2.13 (1H), 1.89-1.93(1H), 1.70-1.73 (1H), 1.44-1.47 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of2,4-Dimethoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

Cis-rac 2,4-Dimethoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to preparative chiral-SFC (Chiralcel OD-H column, MeOH,30%) to give cis-EN1 SC-245 and cis-EN2 SC-246.

[cis-EN1] SC-245—analytical chiral SFC: Chiralcel OD-H (250×4.6 mm 5μ),0.5% DEA in MeOH 30%, 3 g/min, Ret. Time 2.09; ee>95%

[cis-EN2] SC-246—analytical chiral SFC: Chiralcel OD-H (250×4.6 mm 5μ),0.5% DEA in MeOH 30%, 3 g/min, Ret. Time 2.77; ee>95%

2-Methoxy-4-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 50)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.20-8.22 (2H), 8.08 (1H), 8.03 (1H),7.94-7.97 (1H), 6.62 (1H), 4.64-4.66 (1H), 4.02-4.05 (1H), 3.82 (3H),3.70-3.74 (1H), 2.23 (3H), 2.10-2.15 (1H), 2.01-2.07 (1H), 1.65-1.68(1H), 1.48-1.52 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of2-Methoxy-4-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

Cis-rac2-Methoxy-4-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to preparative chiral-SFC (Chiralpak AD-H column, MeOH,15%) to give cis-EN1 SC-248 and cis-EN2 SC-249.

[cis-EN1] SC-248—analytical chiral SFC: Chiralpak AS-H (250×4.6 mm 5μ),0.5% DEA in MeOH 10%, 3 g/min, Ret. Time 2.66; ee>95%

[cis-EN2] SC-249—analytical chiral SFC: Chiralpak AS-H (250×4.6 mm 5μ),0.5% DEA in MeOH 10%, 3 g/min, Ret. Time 3.42; ee>95%

[trans]-rac2-Methoxy-4-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-252

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.22-8.24 (2H), 8.10 (2H), 7.97-8.00(1H), 6.64 (1H), 5.18-5.20 (1H), 4.17-4.22 (1H), 3.97-4.01 (1H), 3.81(3H), 2.28-2.35 (4H), 2.14-2.18 (1H), 1.84-1.90 (1H), 1.75-1.79 (1H),1.16 (3H).

2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-4-ol(Example 51)

Sodium thiomethoxide (0.4 g, 5.39 mmol) was added to a solution of2,4-Dimethoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(1.2 g, 2.69 mmol) in dry DMF (15 mL) at RT and the reaction wassubjected to microwave irradiation at 110° C. for 90 min. The RM waspoured into cold water and acidified with dilute HCl solution up topH-7.0. A Solid precipitated. The solid was filtered, washed with waterand dried in vacuo to get2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-4-ol(0.75 g, 68%) as a white solid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.21-8.22 (1H), 8.16-8.18 (1H), 8.05(1H), 7.94-7.97 (1H), 7.87 (1H), 6.13 (1H), 4.62-4.64 (1H), 4.02-4.06(1H), 3.77 (3H), 3.66-3.70 (1H), 2.10-2.15 (1H), 1.87-1.92 (1H),1.73-1.75 (1H), 1.44-1.47 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-4-ol

Cis-rac2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-4-olwas subjected to preparative chiral-SFC (Chiralcel OX-H column, MeOH,35%) to give cis-EN1 SC-250 and cis-EN2 SC-251.

[cis-EN1] SC-250—analytical chiral SFC: Chiralcel OX-H (250×4.6 mm 5μ),0.5% DEA in MeOH 30%, 3 g/min, Ret. Time 1.19; ee>95%

[cis-EN2] SC-251—analytical chiral SFC: Chiralcel OX-H (250×4.6 mm 5μ),0.5% DEA in MeOH 30%, 3 g/min, Ret. Time 1.46; ee>95%

[cis-EN1]-4-(Difluoro-methoxy)-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 52)

K₂CO₃(0.32 g, 2.32 mmol) was added to clear solution of [cis-EN1] SC-250(0.5 g, 1.16 mmol) in dry DMF (10 mL) at RT. The total reaction mass washeated to 90° C., and purged with Freon gas (CHF₂Cl) for 30 min. The RMwas diluted with water (50 mL) and extracted with EtOAc (50 mL×2). Theorganic extract was washed with water (2×50 mL), brine (100 mL), dried(Na₂SO₄) and concentrated under reduced pressure to get crude compound.The crude compound was purified by CC (0-20% EtOAc in PE) to obtain[cis-EN1]-2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-4-ol(0.14 g, 26%) as a white solid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.18-8.22 (2H), 8.14 (1H), 8.06 (1H),7.94-7.96 (1H), 7.26-7.51 (1H), 6.58 (1H), 4.66-4.69 (1H), 4.05-4.08(1H), 3.87 (3H), 3.70-3.75 (1H), 2.10-2.16 (1H), 1.95-1.99 (1H),1.70-1.73 (1H), 1.48-1.51 (4H).

NOE: C-2 proton & methyl=cis

[cis-EN1] SC-253—analytical chiral SFC: Amylose C-S-5μ (250×4.6 mm 5μ),0.5% DEA in MeOH 35%, 3 g/min, Ret. Time 2.18; ee>95%

[cis-EN2]-4-(Difluoro-methoxy)-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 52)

K₂CO₃(0.32 g, 2.32 mmol) was added to clear solution of [cis-EN2] SC-251(0.5 g, 1.16 mmol) in dry DMF (10 mL) at RT. The total reaction mass washeated to 90° C., then purged with Freon gas for 30 min. The RM wasdiluted with water (50 mL) and extracted with EtOAc (50 mL×2). Theorganic extract was washed with water (2×50 mL), brine (100 mL), dried(Na2SO4) and concentrated under reduced pressure to get crude compound.The crude compound was purified by CC (0-20% EtOAc in PE) to obtain[cis-EN2]-2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-4-ol(0.16 g, 29%) as a white solid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.18-8.22 (2H), 8.14 (1H), 8.05 (1H),7.93-7.96 (1H), 7.26-7.51 (1H), 6.59 (1H), 4.66-4.69 (1H), 4.05-4.08(1H), 3.86 (3H), 3.70-3.75 (1H), 2.10-2.15 (1H), 1.95-1.99 (1H),1.70-1.73 (1H), 1.47-1.51 (4H).

[cis-EN2] SC-254—analytical chiral SFC: Amylose C-S-5μ (250×4.6 mm 5μ),0.5% DEA in MeOH 35%, 3 g/min, Ret. Time 3.1; ee>95%

3-Fluoro-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 53)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.17-8.21 (2H), 8.06 (1H), 7.94-7.96(2H), 7.60-7.63 (1H), 4.58-4.60 (1H), 4.03-4.06 (1H), 3.93 (3H),3.68-3.72 (1H), 2.11-2.16 (1H), 1.92-1.96 (1H), 1.71-1.74 (1H),1.47-1.50 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of3-Fluoro-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

Cis-rac3-fluoro-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to preparative chiral-SFC (LUX Amylose-2 column, MeOH,30%) to give cis-EN1 SC-255 and cis-EN2 SC-256.

[cis-EN1] SC-255—analytical chiral SFC: Lux Amylose-2 (250×4.6 mm 5μ),iPrOH 20%, 3 g/min, Ret. Time 3.52; ee>95%

[cis-EN2] SC-256—analytical chiral SFC: Lux Amylose-2 (250×4.6 mm 5μ),iPrOH 20%, 3 g/min, Ret. Time 4.42; ee>95%

4-Fluoro-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 54)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.17-8.23 (3H), 8.07 (1H), 7.94-7.97(1H), 6.73-6.75 (1H), 4.70-4.73 (1H), 4.02-4.05 (1H), 3.87 (3H),3.69-3.74 (1H), 2.10-2.16 (2H), 1.65-1.68 (1H), 1.48-1.51 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of4-Fluoro-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

Cis-rac4-fluoro-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to preparative chiral-SFC (Chiralpak AD-H column, 0.5% DEAin MeOH, 25%) to give cis-EN1 SC-257 and cis-EN2 SC-258.

[cis-EN1] SC-257—analytical chiral SFC: Chiralpak AD-H (250×4.6 mm 5μ),0.5% DEA in MeOH, 25%, 3 g/min, Ret. Time 2.56; ee>95%

[cis-EN2] SC-258—analytical chiral SFC: Chiralpak AD-H (250×4.6 mm 5μ),0.5% DEA in MeOH, 25%, 3 g/min, Ret. time 3.2; ee>95%

[trans]-rac4-fluoro-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-259

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.22-8.25 (3H), 8.10 (1H), 7.97-8.00(1H), 6.75-6.77 (1H), 5.27-5.29 (1H), 4.18-4.22 (1H), 4.00-4.03 (1H),3.87 (3H), 2.18-2.26 (1H), 1.79-1.92 (2H), 1.18 (3H).

2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-isonicotinonitrile(Example 55)

Step 1:2-methoxy-5-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyridin-4-yltrifluoromethanesulfonate

TEA (1.46 mL, 10.44 mmol) was added to a solution of2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-4-ol(1.5 g, 3.48 mmol) in dichloromethane at 0° C., thentrifluoromethanesulfonic anhydride (1.2 mL, 6.96 mmol) was added slowlydrop by drop at same temperature. After completion of addition thereaction was warmed to RT and stirred at this temperature for 5 h. Themixture was diluted with water (250 mL) and extracted with DCM (150mL×3). The organic extract was washed with NaHCO3 (100 mL), water (100mL), brine (200 mL), dried (Na₂SO₄) and concentrated under reducedpressure to get2-methoxy-5-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyridin-4-yltrifluoromethanesulfonate (1.9 g, 98%) as a dark brown solid.

Step 2:2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-isonicotinonitrile

Zinc cyanide (625 mg, 5.32 mmol) was added to an Ar purged solution of2-methoxy-5-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyridin-4-yltrifluoromethanesulfonate (2.0 g, 3.55 mmol) in dry DMF (20 mL), Thendppf (157 mg, 0.28 mmol), Zinc powder (69 mg, 1.06 mmol) and Pd₂(dba)₃(97.5 mg, 0.16 m·mol) were added and the reaction was heated to 120° C.for 12 h. The mixture was filtered through celite and washed with EtOAc.The filtrate was diluted with water (50 mL) and extracted with EtOAc (50mL×3). The combined organic extracts were washed with water (100 mL),brine (100 mL), dried (Na₂SO₄) and concentrated under reduced pressureto get the crude product. The crude compound was purified by CC (0-30%EtOAc in PE) to obtain2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-isonicotinonitrile(0.8 g, 51%) as a white solid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.36-8.37 (1H), 8.21-8.22 (1H), 8.09(1H), 7.94-7.97 (1H), 7.39 (1H), 4.74-4.76 (1H), 4.07-4.10 (1H), 3.91(3H), 3.73-3.78 (1H), 2.11-2.17 (2H), 1.78-1.81 (1H), 1.52-1.55 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-isonicotinonitrile

Cis-rac2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-isonicotino-nitrilewas subjected to preparative chiral-SFC (Lux Cellulose-2 column, MeOH,20%) to give cis-EN1 SC-260 and cis-EN2 SC-261.

[cis-EN1] SC-260—analytical chiral SFC: Lux Cellulose-2 (250×4.6 mm 5μ),0.5% DEA in MeOH 30%, 3 g/min, Ret. Time 2.33; ee>95%

[cis-EN2] SC-261—analytical chiral SFC: Lux Cellulose-2 (250×4.6 mm 5μ),0.5% DEA in MeOH 30%, 3 g/min, Ret. Time 2.63; ee>95%

3-Methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 56)

Step 1: 5-bromo-3methylpicolinaldehyde

A solution of BuLi (1.6 M in Hexane; 38 mL, 60 mmol) was added to2,5-dibromo-3-methylpyridine (15.0 g, 60 mmol) in dry DCM (150 mL) underAr at −78° C. over 20 min. The RM was stirred at −78° C. for 30 min andthen dry DMF (5.7 mL, 72 mmol) was added slowly. The RM was slowlywarmed to 0° C. and the RM was maintained at 0° C. for 20 min. Aftercompletion of the reaction, the RM was quenched with sat. NH₄Cl andextracted with DCM. The organic layer was washed with water followed bybrine, dried over Na₂SO₄ and concentrated under reduced pressure to getcrude compound. The crude compound was purified by CC (0-5% EtOAc in PE)to 5-bromo-3methylpicolinaldehyde (3.0 g, 28%) as a light yellow solid.

Step 2: 2-(5-bromo-3-methylpyridi-2y)tetrahydro-2H-pyran-4-ylmethanesulfonate

Methanesulphonic acid (20 mL, 303 mmol) was added to a solution of5-bromo-3methylpicolinaldehyde (2.8 g, 0.018 mol) and 3-buten-1-ol (4.6mL, 45.45 mmol) in DCM (120 mL) at 0° C., stirred at 0° C. for 1 h. Themixture was diluted with water and basified to pH-8.0 by using sat.NaHCO₃ solution. The mixture was extracted with DCM (300 mL) and washedwith water (200 mL), and brine (200 mL), dried over Na2SO4 andconcentrated under reduced pressure to get crude2-(5-bromo-3-methylpyridi-2y)tetrahydro-2H-pyran-4-yl methanesulfonate(6.5 g, 62%) as a brown solid. The crude material was directly used fornext step without further purification.

Step 3:5-bromo-3-methyl-2-(4-(3-(trifluoromethyl)phenylthio)tetrahydro-2H-pyran-2-yl)pyridine

3-Trifluoromethyl thiophenol (4.5 mL, 34.38 mmol) was added to asuspension of 2-(5-bromo-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (6.0 g, 17.19 mmol) and K₂CO₃ (4.8 g, 34.38 mmol) inDMF (120 mL) and the RM was heated at 50° C. for 5 h and then stirred atRT for 16 h. After completion of reaction, the mixture was diluted withwater (300 mL) and extracted with EtOAc (250 mL×2). The organic extractwas washed with water (200 mL), brine (200 mL), dried (Na2SO4) andconcentrated under reduced pressure to get crude compound. The crudecompound was purified by CC (silica gel 100-200 mesh, 0-10% EtOAc in PE)to obtain5-bromo-3-methyl-2-(4-(3-(trifluoromethyl)phenylthio)tetrahydro-2H-pyran-2-yl)pyridine(6.0 g, 81%) as a light brown gummy liquid.

Step 4:5-bromo-3-methyl-2-(4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

5-bromo-3-methyl-2-(4-(3-(trifluoromethyl)phenylthio)tetrahydro-2H-pyran-2-yl)pyridine(6.0 g, 13.92 mmol) was dissolved in MeOH (180 mL) and a solution ofOXONE (17.0 g, 27.84 mmol) in water (150 mL) was added. The totalreaction mass was stirred at RT for 18 h. The reaction mass was dilutedwith water (100 mL) and extracted with EtOAc (3×100 mL). The combinedorganic extract was washed with water (100 mL), brine (100 mL), driedover Na₂SO₄ and concentrated to get crude. The crude compound waspurified by CC (0-30% EtOAc in PE) to obtain5-bromo-3-methyl-2-(4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(3.5 g, 55%) as a white solid.

Step 5:5-bromo-3-methyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

A solution of5-bromo-3-methyl-2-(4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(3.5 g, 7.55 mmol) in THF (30 mL) was cooled to −78° C. and t-BuOK (1Msolution in THF) (15 mL, 15.11 mmol) was added drop-wise. The totalreaction mass was stirred at −78° C. for 30 min, then Mel (1.2 mL, 18.89mmol) was added and the resulting mixture was warmed to RT and stirredfor 16 h. The reaction mass was diluted with EtOAc (150 mL) and washedwith water (100 mL) and brine (100 mL), dried over Na2SO4 andconcentrated under reduced pressure to get crude compound. The crudecompound was purified by CC (0-20% EtOAc in PE) to get5-bromo-3-methyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)-tetrahydro-2H-pyran-2-yl)pyridine(1.6 g, 45%) as a white solid.

Step 6:3-methyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylthio)pyridine

Xantphos (126 mg, 0.22 mmol) followed by Pd₂(dba)₃ (201 mg, 0.22 mmol)were added to a degassed solution of5-bromo-3-methyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(1.5 g, 3.14 mmol) and DIPEA (1.2 mL, 21.97 mmol) in toluene (50 mL) andfurther degassed for 10 min. Sodium thiomethoxide (1.1 g, 6.28 mmol) wasadded and further degassed for 5 min. The resulting mixture was heatedat 120° C. for 16 h under Ar. Reaction mass was filtered through celitebed and washed the cake with EtOAc (50 mL). The filtrate concentrated toyield crude product. The crude product was purified by CC (0-30% EtOAcin PE) to obtain3-methyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylthio)pyridine(1.3 g, 93%) as off white solid.

Step 7:3-methyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine

3-methyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylthio)pyridine(1.5 g, 3.37 mmol) was dissolved in MeOH (45 mL) and a solution of OXONE(4.1 g, 6.74 mmol) in water (37.5 mL) was added and stirred at RT for 18h. The reaction mass was diluted with water (50 mL) and extracted withEtOAc (3×100 mL). The organic extract was washed with brine (100 mL),dried over Na₂SO₄ and concentrated to get crude. The crude compound waspurified by CC (0-50% EtOAc in PE) to obtain3-methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(1.0 g, 63%) as a white solid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.86 (1H), 8.23-8.24 (1H), 8.20-8.21(1H), 8.08 (1H), 7.97-8.00 (1H), 4.87-4.89 (1H), 3.98-4.01 (1H),3.76-3.80 (1H), 3.30 (3H), 2.60-2.64 (1H), 2.46 (3H), 2.10-2.15 (1H),1.69-1.72 (1H), 1.52 (3H), 1.45-1.48 (1H).

NOE: C-2 proton & methyl=cis

Chiral resolution of3-methyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine

Cis-rac3-Methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to preparative chiral-SFC (Chiralpak AS-H column, MeOH,35%) to give cis-EN1 SC-262 and cis-EN2 SC-263.

[cis-EN1] SC-262—analytical chiral SFC: Chiralpak AS-H (250×4.6 mm 5μ),0.5% DEA in MeOH 15%, 3 g/min, Ret. Time 4.3; ee>95%

[cis-EN2] SC-263—analytical chiral SFC: Chiralpak AS-H (250×4.6 mm 5μ),0.5% DEA in MeOH 15%, 3 g/min, Ret. Time 6.7; ee>95%

The following compounds (Examples 35 to 45 and 57 to 60) were preparedfrom the aldehydes described above or from commercially availablealdehydes or from intermediates described within this application inanalogy to3-methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 56).

2-[4-[[3-(Difluoro-methyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methylsulfonyl-5-(trifluoromethyl)-pyridine(Example 35)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=9.32 (1H), 8.55 (1H), 8.02-8.05 (3H),7.86-7.89 (1H), 7.12-7.31 (1H), 5.40-5.42 (1H), 4.05-4.08 (1H),3.74-3.79 (1H), 3.43 (3H), 2.53-2.57 (1H), 2.13-2.18 (1H), 1.83-1.86(1H), 1.46-1.50 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of2-[4-[[3-(Difluoro-methyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methylsulfonyl-5-(trifluoromethyl)-pyridine

Cis-rac2-[4-[[3-(Difluoro-methyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methylsulfonyl-5-(trifluoromethyl)-pyridinewas subjected to preparative chiral-SFC (Chiralpak OJ-H column, MeOH,20%) to give cis-EN1 SC-212 and cis-EN2 SC-213.

[cis-EN1] SC-212—analytical chiral SFC: Chiralpak OJ-H (250×4.6 mm 5μ),MeOH, 10%, 3 g/min, Ret. Time 3.19; ee>95%

[cis-EN2] SC-213—analytical chiral SFC: Chiralpak OJ-H (250×4.6 mm 5μ),MeOH, 10%, 3 g/min, Ret. time 4.93; ee>95%

2-[4-Methyl-4-[(3-methylsulfonyl-phenyl)sulfonyl]-tetrahydro-pyran-2-yl]-3-methylsulfonyl-5-(trifluoromethyl)-pyridine

Step 1:2-(4-methyl-4-((3-(methylthio)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)pyridine

A solution of3-chloro-2-(4-methyl-4-((3-(trifluoromethoxy)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)pyridine(2.1 g, 4.2 mmol) and NaSMe (1.51 g, 16.80 mmol) in pyridine (30 mL) washeated at 60° C. for 16 h under Ar. The RM was diluted with water (20mL) and the organic product was extracted with EtOAc (3×50 mL). Thecombined organic layer was washed with brine, dried over anhydr. Na₂SO₄,filtered and evaporated the solvent under vacuo to give crude, which waspurified by CC (0-15% EtOAc in PE as eluent) to get crude2-(4-methyl-4-((3-(methylthio)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)pyridine(1.7 g). The crude was purified by SFC using the below condition andevaporating the fractions to get2-(4-methyl-4-(3-(trifluoromethoxy)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)pyridine(500 mg, 23%) as a white solid and 900 mg of2-(4-methyl-4-((3-(methylthio)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)-pyridineas a white solid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.70 (1H), 8.00 (1H), 7.67-7.69 (1H),7.59-7.64 (3H), 4.81-4.83 (1H), 3.98-4.01 (1H), 3.69-3.74 (1H), 2.56(6H), 2.07-2.12 (1H), 1.69-1.72 (1H), 1.45-1.50 (4H).

Step 2:2-[4-Methyl-4-[(3-methylsulfonyl-phenyl)sulfonyl]-tetrahydro-pyran-2-yl]-3-methylsulfonyl-5-(trifluoromethyl)-pyridine

2-(4-methyl-4-((3-(methylthio)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)pyridine(200 mg, 0.41 mmol) dissolved in CH3CN (20 mL)-THF (20 mL) and asolution of oxone (1.3 g, 2.09 mmol) in water (5 mL) was added. The RMwas stirred at 40° C. for 16 h. The RM was concentrated in vacuo, theresidue was diluted with water (50 mL) and the organic product wasextracted with DCM (3×50 mL). The combined organic extract was washedwith brine (2×50 mL), dried over anhydr. Na₂SO₄ and concentrated to getcrude product. The crude compound was purified by CC (silica gel 60-120mesh, 0-50% EtOAc in PE) to obtain2-[4-methyl-4-[(3-methylsulfonyl-phenyl)sulfonyl]-tetrahydro-pyran-2-yl]-3-methylsulfonyl-5-(trifluoromethyl)-pyridine(135 mg) as a solid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=9.32 (1H), 8.56 (1H), 8.37-8.39 (1H),8.28 (1H), 8.21-8.22 (1H), 7.99-8.02 (1H), 5.42-5.44 (1H), 4.06-4.09(1H), 3.75-3.80 (1H), 3.44 (3H), 2.54-2.56 (1H), 2.13-2.19 (1H),1.87-1.92 (1H), 1.48-1.52 (4H).

3-Chloro-2-[4-[[3-fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine(Example 36)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=9.0-9.02 (1H), 8.46-8.47 (1H) 8.25-8.27(1H), 8.07-8.09 1(H), 7.93 (1H), 5.03-5.06 (1H), 4.02-4.05 (1H),3.74-3.79 (1H), 3.38 (3H) 2.52-2.57 (1H), 2.14-2.20 (1H), 1.75-1.791(H), 1.48-1.52 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of3-Chloro-2-[4-[[3-fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine

Cis-rac3-Chloro-2-[4-[[3-fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridinewas subjected to preparative chiral-SFC (Chiralpak IC column, MeOH, 50%)to give cis-EN1 SC-214 and cis-EN2 SC-215.

[cis-EN1] SC-214—analytical chiral SFC: Chiralpak IC (250×4.6 mm 5μ),MeOH, 40%, 3 g/min, Ret. Time 2.02; ee>95%

[cis-EN2] SC-215—analytical chiral SFC: Chiralpak IC (250×4.6 mm 5μ),MeOH, 40%, 3 g/min, Ret. time 4.33; ee>95%

3-Chloro-2-[4-[[3-(difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine(Example 37)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=9.02-9.03 (1H), 8.46-8.47 (1H), 7.95-7.97(1H), 7.89-7.91 (2H), 7.12-7.31 (1H), 5.04-5.06 (1H), 4.02-4.05 (1H),3.75-3.79 (1H), 3.39 (3H), 2.52-2.57 (1H), 2.13-2.19 (1H), 1.74-1.77(1H), 1.48-1.52 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of3-Chloro-2-[4-[[3-(difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine

Cis-rac3-chloro-2-[4-[[3-(difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridinewas subjected to preparative chiral-SFC (Chiralpak AS-H column, MeOH,30%) to give cis-EN1 SC-216 and cis-EN2 SC-217.

[cis-EN1] SC-216—analytical chiral SFC: Chiralpak AS-H (250×4.6 mm 5μ),MeOH, 20%, 3 g/min, Ret. Time 3.15; ee>95%

[cis-EN2] SC-217—analytical chiral SFC: Chiralpak AS-H (250×4.6 mm 5μ),MeOH, 20%, 3 g/min, Ret. time 3.7; ee>95%

3-Chloro-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 38)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=9.00-9.01 (1H), 8.45 (1H), 7.90-7.92(1H), 7.85-7.87 (2H), 7.76-7.77 (1H), 5.01-5.04 (1H), 4.01-4.04 (1H),3.74-3.79 (1H), 3.38 (3H), 2.47-2.52 (1H), 2.10-2.15 (1H), 1.69-1.72(1H), 147-1.50 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of3-chloro-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

Cis-rac3-chloro-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to preparative chiral-SFC (Chiralpak AS-H column, MeOH,35%) to give cis-EN1 SC-218 and cis-EN2 SC-219.

[cis-EN1] SC-218—analytical chiral SFC: Lux Cellulose-2 (250×4.6 mm 5μ),0.5% DEA in MeOH, 35%, 3 g/min, Ret. Time 4.49; ee>95%

[cis-EN2] SC-219—analytical chiral SFC: Lux Cellulose-2 (250×4.6 mm 5μ),0.5% DEA in MeOH, 35%, 3 g/min, Ret. time 5.12; ee>95%

3-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(Example 39)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=9.32 (1H), 8.56 (1H), 7.89-7.92 (1H),7.84-7.87 (2H), 7.77 (1H), 5.40-5.42 (1H), 4.06-4.08 (1H), 3.75-3.79(1H), 3.42 (3H), 2.50-2.54 (1H), 2.11-2.18 (1H), 1.83-1.86 (1H),1.47-1.51 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of3-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine

Cis-rac3-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridinewas subjected to preparative chiral-SFC (Chiralpak IE column, 0.5% DEAin MeOH, 25%) to give cis-EN1 SC-220 and cis-EN2 SC-221.

[cis-EN1] SC-220—analytical chiral SFC: Chiralpak IE (250×4.6 mm 5μ),0.5% DEA in MeOH, 25%, 3 g/min, Ret. Time 1.62; ee>95%

[cis-EN2] SC-221—analytical chiral SFC: Chiralpak IE (250×4.6 mm 5μ),0.5% DEA in MeOH, 25%, 3 g/min, Ret. time 1.95; ee>95%

5-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-pyridine(Example 40)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=9.35 (1H), 8.60-8.61 (1H), 8.22-8.24(1H), 8.18-8.20 (1H), 8.07 (1H), 7.96-7.97 (1H), 4.90-4.92 (1H),4.03-4.06 (1H), 3.73-3.76 (1H), 3.44 (3H), 2.57-2.61 (1H), 2.14-2.20(1H), 1.72-1.75 (1H), 1.47-1.50 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of5-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-pyridine

Cis-rac5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-pyridinewas subjected to preparative chiral-SFC (Chiralpak AD-H column, MeOH,35%) to give cis-EN1 SC-222 and cis-EN2 SC-223.

[cis-EN1] SC-222—analytical chiral SFC: Chiralpak AD-H (250×4.6 mm 5μ),MeOH, 30%, 3 g/min, Ret. Time 1.61; ee>95%

[cis-EN2] SC-223—analytical chiral SFC: Chiralpak AD-H (250×4.6 mm 5μ),MeOH, 30%, 3 g/min, Ret. time 2.08; ee>95%

3-Methoxy-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 41)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.62 (1H), 8.21-8.23 (1H), 8.17-8.18(1H), 8.05 (1H), 7.95-7.98 (1H), 7.86 (1H), 4.98-5.00 (1H), 3.97-4.00(1H), 3.93 (3H), 3.68-3.72 (1H), 3.34 (3H), 2.50-2.54 (1H), 2.09-2.14(1H), 1.57-1.60 (1H), 1.45-1.49 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of3-Methoxy-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-Pyran-2-yl]-pyridine

Cis-rac3-methoxy-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to preparative chiral-SFC (Chiralpak IC column, MeOH, 40%)to give cis-EN1 SC-224 and cis-EN2 SC-225.

[cis-EN1] SC-224—analytical chiral SFC: Chiralpak IC (250×4.6 mm 5μ),MeOH, 40%, 4 g/min, Ret. Time 2.86; ee>95%

[cis-EN2] SC-225—analytical chiral SFC: Chiralpak IC (250×4.6 mm 5μ),MeOH, 40%, 4 g/min, Ret. time 9.47; ee>95%

5-Chloro-3-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 42)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.97 (1H), 8.35-8.36 (1H), 8.22-8.24(1H), 8.18-8.20 (1H), 8.07 (1H), 7.96-7.99 (1H), 5.33-5.35 (1H),4.03-4.06 (1H), 3.71-3.75 (1H), 3.39 (3H), 2.55-2.59 (1H), 1.13-2.18(1H), 1.79-1.82 (1H), 1.46-1.49 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of5-Chloro-3-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-Pyran-2-yl]-pyridine

Cis-rac5-chloro-3-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to preparative chiral-SFC (Chiralpak IC column, 0.5% DEAin MeOH, 30%) to give cis-EN1 SC-226 and cis-EN2 SC-227.

[cis-EN1] SC-226—analytical chiral SFC: Chiralpak IC (250×4.6 mm 5μ),0.5% DEA in MeOH, 30%, 3 g/min, Ret. Time 3.45; ee>95%

[cis-EN2] SC-227—analytical chiral SFC: Chiralpak IC (250×4.6 mm 5μ),0.5% DEA in MeOH, 30%, 3 g/min, Ret. time 5.01; ee>95%

3-(Methylsulfinyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(Example 43)

Chiral resolution of2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)pyridine

[Cis-rac]2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)pyridinewas subjected to preparative chiral-SFC (Chiralpak-AD-H column, 0.5% DEAin MeOH, 40%)) to give[cis-EN1]-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)pyridineand[cis-EN2]-2-(4-methyl-4-(3-(trifluoromethyl)phenyl-sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)pyridine.

[cis-EN1]-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)pyridine(900 mg, 1.80 mmol) dissolved in MeOH (36 mL), water (10 mL) and sodiumperiodate (770 mg, 3.60 mmol) was added. The RM was stirred at RT for 47h. The RM was concentrated in vacuo; the resulting residue was dilutedwith water (10 mL) and the organic product was extracted with DCM (3×20mL). The combined organic extract was washed with brine (2×25 mL), dried(anhydr. Na₂SO₄) and concentrated to get the crude product. The crudecompound was purified by CC (0-30% EtOAc in PE) to obtain an epimericmixture [Epi-Mix1] of3-(Methylsulfinyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(750 mg, 80%) as a solid.

Purification of[Epi-Mix1]-3-(Methylsulfinyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine

[Epi-Mix1]-3-(Methylsulfinyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridinewas subjected to preparative HPLC (X-bridge C18, 10 mM ammoniumacetate/MeCN)) to give [EN1] SC-229 and [EN2] SC-230.

[EN1] SC-229—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 3 g/min,RT, 0.5% DEA in MeOH, 15%, Ret. Time 1.91; ee>95; [α]₂₅ ⁵⁸⁹ (c=1.0,CHCl₃)=+97.4°; NOE: C-2 proton & methyl=cis; 1H-NMR (600 MHz,[d₆]-DMSO): δ=9.04 (1H), 8.64 (1H), 8.18-8.22 (2H, 8.08 (1H), 7.93-7.96(1H), 4.96-4.98 (1H), 4.10-4.13 (1H), 3.73-3.78 (1H), 3.07 (3H),2.28-2.32 (1H), 2.17-2.22 (1H), 1.85-1.89 (1H), 1.50-1.54 (4H).

[EN2] SC-230—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 3 g/min,RT, 0.5% DEA in MeOH, 15%, Ret. Time 7.92; ee>95%; [α]₂₅ ⁵⁸⁹ (c=1.0,CHCl₃)=−63.6°; 1H-NMR (600 MHz, [d6]-DMSO): δ=9.10-9.11 (1H), 8.61 (1H),8.20-8.24 (1H), 8.08 (1H), 7.97-8.00 (1H), 4.93-4.95 (1H), 4.03-4.06(1H), 3.75-3.79 (1H), 2.82 (3H), 2.42-2.46 (1H), 2.07-2.12 (2H),1.47-1.49 (4H).

[cis-EN2]-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)pyridine(850 mg, 1.75 mmol) dissolved in MeOH (36 mL), water (10 mL) and sodiumperiodate (750 mg, 3.50 mmol). The total reaction mass was stirred at RTfor 47 h. The RM was concentrated in vacuo, the residue was diluted withwater (10 mL) and extracted with DCM (3×20 mL). The combined organicextract was washed with brine (2×25 mL), dried (Na₂SO₄) and concentratedto get crude. The crude compound was purified by CC (0-30% EtOAc in PE)to obtain[Epi-Mix2]-3-(methylsulfinyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(750 mg, 80%) as a solid.

Purification of[Epi-Mix2]-3-(Methylsulfinyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-Pyran-2-yl]-5-(trifluoromethyl)-pyridine

[Epi-Mix2]-3-(Methylsulfinyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridinewas subjected to preparative HPLC (X-bridge C18, 10 mM ammoniumacetate/MeCN)) to give [EN3] SC-231 and [EN4] SC-228.

[EN3] SC-231—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 3 g/min,RT, 0.5% DEA in MeOH, 15%, Ret. Time 4.24; ee>95; [α]₂₅ ⁵⁸⁹ (c=1.0,CHCl₃)=−137.7°; NOE: C-2 proton & methyl=cis; ¹H-NMR (600 MHz,[d6]-DMSO): δ=9.04 (1H), 8.64 (1H), 8.18-8.22 (2H, 8.08 (1H), 7.93-7.96(1H), 4.96-4.98 (1H), 4.10-4.13 (1H), 3.73-3.78 (1H), 3.07 (3H),2.28-2.32 (1H), 2.17-2.22 (1H), 1.85-1.89 (1H), 1.50-1.54 (4H).

[EN4] SC-228—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 3 g/min,RT, 0.5% DEA in MeOH, 15%, Ret. Time 2.3; ee>95%; [α]₂₅ ⁵⁸⁹ (c=1.0,CHCl₃)=+61.0°; 1H-NMR (600 MHz, [d6]-DMSO): δ=9.10-9.11 (1H), 8.61 (1H),8.20-8.24 (1H), 8.08 (1H), 7.97-8.00 (1H), 4.93-4.95 (1H), 4.03-4.06(1H), 3.75-3.79 (1H), 2.82 (3H), 2.42-2.46 (1H), 2.07-2.12 (2H),1.47-1.49 (4H).

3-Chloro-5-(methylsulfinyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 44)

Chiral resolution of3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfinyl)pyridine

[Cis-rac]3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfinyl)pyridinewas subjected to preparative chiral-SFC (Chiralcel-OD-H column, MeOH,40%)) to give[cis-EN1]-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfinyl)pyridineand[cis-EN2]-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfinyl)pyridine.

NOE: C-2 proton & methyl=cis

Sodium metaperiodate (0.45 g, 2.15 mmol) was added to a stirred solutionof[cis-EN1]-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfinyl)pyridine(0.5 g, 1.07 mmol) in MeOH (50 mL), water (10 mL) and stirred for 24 hat RT. The RM was concentrated under reduced pressure to remove MeOH.The Aq. layer was diluted with water (100 mL), extracted with DCM (3×50mL). The combined organic layer was washed with brine (50 mL), dried(Na₂SO₄), filtered and evaporated the solvent under vacuo to give crude,which was purified by CC (5% MeOH in dichloromethane) to give[Epi-Mix1]-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)-sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfinyl)pyridine(0.35 g, 68%) as off white solid.

Chiral resolution of[Epi-Mix1]-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfinyl)pyridine

[Epi-Mix1]-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfinyl)pyridinewas subjected to preparative chiral SFC (Chiralcel OD-H, MeOH, 25%) togive [EN1] SC-232 and [EN2] SC-233.

[EN1] SC-232—analytical SFC: Chiralcel OD-H (250×4.6 mm 5μ), 3 g/min,RT, 0.5% DEA in MeOH, 40%, Ret. Time 3.28; ee>95; [α]₂₅ ⁵⁸⁹ (c=1.0,CHCl₃)=−80.0°; ¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.80 (1H), 8.18-8.23 (3H),8.07 (1H), 7.96-7.98 (1H), 4.98-5.00 (1H), 4.00-4.03 (1H), 3.72-3.77(1H), 2.90 (3H), 2.53-2.60 (1H), 2.11-2.16 (1H), 1.69-1.72 (1H),1.45-1.50 (4H).

[EN2] SC-233—analytical SFC: Chiralcel OD-H (250×4.6 mm 5μ), 3 g/min,RT, 0.5% DEA in MeOH, 40%, Ret. Time 3.65; ee>95%; [α]₂₅ ⁵⁸⁹ (c=1.0,CHCl₃)=−23.6°; 1 H-NMR (600 MHz, [d6]-DMSO): δ=8.79 (1H), 8.18-8.23(3H), 8.07 (1H), 7.96-7.99 (1H), 4.98-5.00 (1H), 4.00-4.03 (1H),3.72-3.77 (1H), 2.90 (3H), 2.56-2.60 (1H), 2.10-2.16 (1H), 1.69-1.72(1H), 1.46-1.50 (4H).

Sodium metaperiodate (0.45 g, 2.15 mmol) was added to a stirred solutionof[cis-EN2]-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfinyl)pyridine(0.5 g, 1.07 mmol) in MeOH (50 mL), Water (10 mL) and stirred for 24 hat RT. The RM was concentrated under reduced pressure to remove MeOH.The Aq. layer was diluted with water (100 mL), extracted with DCM (3×50mL). The combined organic layer was washed with brine (50 mL), dried(Na₂SO₄), filtered and evaporated the solvent under vacuo to give crude,which was purified by CC (5% MeOH in DCM) to give[Epi-Mix2]-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-tetrahydro-2H-pyran-2-yl)-5-(methylsulfinyl)pyridine(0.39 g, 76%) as an off white solid. Chiral resolution of[Epi-Mix2]-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfinyl)pyridine[Epi-Mix2]-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfinyl)pyridinewas subjected to preparative chiral SFC (Chiralcel OD-H, MeOH, 45%) togive [EN3] SC-234 and [EN4] SC-235.

[EN3] SC-234—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 3 g/min,RT, 0.5% DEA in MeOH, 15%, Ret. Time 4.08; ee>95; [α]₂₅ ⁵⁸⁹ (c=1.0,CHCl₃)=+104°; ¹H-NMR (600 MHz, [d6]-DMSO): δ=8.80 (1H), 8.18-8.23 (3H),8.07 (1H), 7.96-7.98 (1H), 4.98-5.00 (1H), 4.00-4.03 (1H), 3.71-3.76(1H), 2.86 (3H), 2.53-2.60 (1H), 2.11-2.16 (1H), 1.69-1.72 (1H),1.45-1.52 (4H).

[EN4] SC-235—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 3 g/min,RT, 0.5% DEA in MeOH, 15%, Ret. Time 5.23; ee>95%; [α]₂₅ ⁵⁸⁹ (c=1.0,CHCl₃)=+18.0°; 1H-NMR (600 MHz, [d6]-DMSO): δ=8.80 (1H), 8.18-8.23 (3H),8.07 (1H), 7.96-7.99 (1H), 4.98-5.00 (1H), 4.00-4.03 (1H), 3.72-3.77(1H), 2.90 (3H), 2.56-2.60 (1H), 2.10-2.15 (1H), 1.69-1.71 (1H),1.46-1.50 (4H).

3-Chloro-5-(difluoro-methyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 45)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.76-8.77 (1H), 8.18-8.23 (3H), 8.07(1H), 7.92-7.98 (1H), 7.06-7.26 (1H), 4.98-5.00 (1H), 4.00-4.09 (1H),3.72-3.77 (1H), 3.41 (3H), 2.55-2.60 (1H), 2.11-2.16 (1H), 1.68-1.71(1H), 1.46-1.50 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of3-Chloro-5-(difluoro-methyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

Cis-rac3-Chloro-5-(difluoro-methyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to preparative chiral-SFC (Chiralpak IC column, 0.5% DEAin MeOH, 40%) to give cis-EN1 SC-236 and cis-EN2 SC-237.

[cis-EN1] SC-236—analytical chiral SFC: Chiralpak IC (250×4.6 mm 5μ),MeOH, 40%, 3 g/min, Ret. Time 1.73; ee>95%

[cis-EN2] SC-237—analytical chiral SFC: Chiralpak IC (250×4.6 mm 5μ),MeOH, 40%, 3 g/min, Ret. time 4.43; ee>95%

3-Chloro-2-[4-[[3-(difluoro-methyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine(Example 57)

¹H-NMR (600 MHz, [d₆]-DMSO): δ=9.01 (1H), 8.45 (1H), 8.02-8.05 (3H),7.86-7.88 (1H), 7.12-.7.31 (1H), 5.02-5.04 (1H), 4.01-4.04 (1H),3.74-3.78 (1H), 3.39 (3H), 2.49-2.53 (1H), 2.06-2.15 (1H), 1.70-1.73(1H), 1.41-1.56 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of3-Chloro-2-[4-[[3-(difluoro-methyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine

Cis-rac3-chloro-2-[4-[[3-(difluoro-methyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridinewas subjected to preparative chiral-SFC (Lux Cellulose-2 column, MeOH,45%) to give cis-EN1 SC-264 and cis-EN2 SC-265.

[cis-EN1] SC-264—analytical chiral SFC: Lux Cellulose-2 (250×4.6 mm 5μ),0.5% DEA in MeOH, 40%, 3 g/min, Ret. Time 5.7; ee>95%

[cis-EN2] SC-265—analytical chiral SFC: Lux Cellulose-2 (250×4.6 mm 5μ),0.5% DEA in MeOH, 40%, 3 g/min, Ret. time 7.02; ee>95%

5-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylsulfonyl)pyridine(Example 58)

Step 1:2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridin-3-ol

A solution of3-chloro-5-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(3.7 g, 7.60 mmol) and NaSMe (0.64 g, 9.12 mmol) in pyridine (50 mL) washeated at 60° C. for 12 h under Ar.

The RM was diluted with water (20 mL) and the organic product wasextracted with EtOAc (3×50 mL). The combined organic layer was washedwith brine, dried over anhydr. Na₂SO₄, filtered and evaporated thesolvent under vacuo to get the crude. The crude product was submitted toSFC to get 1.2 g of a mixture of5-(difluoromethoxy)-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)pyridineand3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)-sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylthio)pyridine.The mixture was directly taken for the next step without furtherpurification.

Step 2:5-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylsulfonyl)pyridine

The mixture of5-(difluoromethoxy)-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)pyridineand3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylthio)pyridine(1.2 g, 2.41 mmol) was dissolved in MeOH (42 mL) and a solution of oxone(3.0 g, 4.82 mmol) in water (30 mL) was added. The RM was stirred at RTfor 16 h. MeOH was concentrated in vacuo; the residue was diluted withwater (150 mL) and the organic product was extracted with EtOAc (3×50mL). The combined organic extract was washed with water, brine (100 mL),dried over anhydr. Na₂SO₄ and solvent was concentrated under reducedpressure to get crude product. The crude compound was purified by CC(0-30% EtOAc in PE) to obtain5-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylsulfonyl)pyridine(0.4 g, 31%) as a white solid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.82 (1H), 8.23-8.24 (1H), 8.19-8.20(1H), 8.10 (1H), 8.07 (1H), 7.96-7.99 (1H), 5.33-5.36 (1H), 4.03-4.06(1H), 3.71-3.75 (1H), 3.34 (3H), 2.59-2.63 (1H), 2.13-2.18 (1H),1.77-1.80 (1H), 1.47-1.50 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of5-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylsulfonyl)pyridine

Cis-rac5-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylsulfonyl)pyridinewas subjected to preparative chiral-SFC (Chiralcel OJ-H column, MeOH,20%) to give cis-EN1 SC-266 and cis-EN2 SC-267.

[cis-EN1] SC-266—analytical chiral SFC: Chiralcel OJ-H (250×4.6 mm 5μ),MeOH, 20%, 3 g/min, Ret. Time 1.97; ee>95%

[cis-EN2] SC-267—analytical chiral SFC: Chiralcel OJ-H (250×4.6 mm 5μ),MeOH, 20%, 3 g/min, Ret. time 2.64; ee>95%

3-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine(Example 59)

Step 1:2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridin-3-ol

Sodium thiomethoxide (0.283 g, 4.04 mmol) was added to a clear solutionof3-methoxy-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine(0.500 g, 1.01 mmol) in dry DMF (4 mL) at RT in microwave tube and thereaction mass was subjected to microwave irradiation at 120° C. for 90min. The reaction mass was poured into cold water and acidified withdilute HCl solution up to pH-7.0. The solid product was precipitated outwhich was filtered, washed with water and dried in vacuo for 2 h to get2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridin-3-ol(0.290 g, 60%) as a pale yellow solid.

Step 2:3-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine

To stirred solution of2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridin-3-ol(0.700 g, 1.46 mmol) in dry DMF (10 mL) was added K₂CO₃ (0.403 g, 2.92mmol) at RT. The RM was heated to 90° C. and purged with freon gas(CF₂ClH) for 30 min. The RM was diluted with water (50 mL) and theorganic product was extracted with EtOAc (50 mL×2). The organic extractwas washed with water (2×50 mL), brine (100 mL), dried (anhydr. Na₂SO₄)and concentrated under reduced pressure to get crude compound. The crudecompound was purified by CC (0-30% EtOAc in PE) to obtain racemic3-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine(0.360 g, 50%) as a white solid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.96 (1H), 8.22-8.24 (1H), 8.18-8.20(1H), 8.13 (1H), 8.07 (1H), 7.96-7.98 (1H), 7.23-7.46 (1H), 4.95-4.98(1H), 4.01-4.04 (1H), 3.71-3.76 (1H), 3.39 (3H), 2.50-2.52 (1H),2.11-2.16 (1H), 1.66-1.69 (1H), 1.47-1.53 (4H).

NOE: C-2 proton & methyl=cis

Chiral resolution of3-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine

Cis-rac3-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridinewas subjected to preparative chiral-SFC (Chiralpak IC column, MeOH, 40%)to give cis-EN1 SC-268 and cis-EN2 SC-269.

[cis-EN1] SC-268—analytical chiral SFC: Chiralpak IC (250×4.6 mm 5μ),MeOH, 40%, 4 g/min, Ret. Time 1.48; ee>95%

[cis-EN2] SC-269—analytical chiral SFC: Chiralpak IC (250×4.6 mm 5μ),MeOH, 40%, 4 g/min, Ret. time 2.49; ee>95%

[cis-EN1]-3-cyclopropyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine(Example 60)

A solution of[cis-EN1]-3-chloro-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine(0.25 g, 0.50 mmol), K₃PO₄ (0.26 mL, 1.25 mmol) and 20%tricyclehexylphosphine in toluene (0.49 mL, 0.35 mmol) in toluene (18mL)/water (2 mL) was degassed for 10 min. To the RM was added cyclpropylboronic acid (98 mg, 1.15 mmol) and degassed again for 10 min.Catalytic Pd(OAc)₂ (23 mg, 0.035 mmol) was added and further degassedfor 5 min. The resulting mixture was heated to reflux for 16 h under Ar.Reaction mass was filtered through celite and the filtrate was dilutedwith water (50 mL) and the organic product was extracted with EtOAc(3×50 mL). The combined organic extract was washed with brine (200 mL),dried (anhydr. Na₂SO₄) and concentrated to get crude. The crude productwas purified by CC (0-35% EtOAc in PE) to give[cis-EN1]-3-cyclopropyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine(170 mg, 68%) as liquid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.82-8.84 (1H), 8.19-8.24 (2H), 8.08(1H), 7.97-7.99 (1H), 7.79 (1H), 5.13-5.16 (1H), 4.00-4.04 (1H),3.77-3.82 (1H), 3.31 (3H), 2.62-2.67 (1H), 2.26-2.31 (1H), 2.13-2.18(1H), 1-70-1.73 (1H), 1.49-1.53 (4H), 1.00-1.07 (2H), 0.86-0.91 (1H),0.72-0.76 (1H).

[cis-EN1] SC-270—analytical chiral SFC: Chiralcel OH-H (250×4.6 mm 5μ),0.5% DEA in MeOH 10%, 3 g/min, Ret. Time 5.05; ee>95%

[cis-EN2]-3-cyclopropyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine(Example 60)

A solution of[cis-EN2]-3-chloro-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine(0.25 g, 0.50 mmol), K₃PO₄ (0.26 mL, 1.25 mmol) and 20%tricyclohexylphosphine in toluene (0.49 mL, 0.35 mmol) in toluene (18mL)/water (2 mL) was degassed for 10 min. To the RM was addedcyclopropylboronic acid (98 mg, 1.15 mmol) and degassed again for 10min. Catalytic Pd(OAc)₂ (23 mg, 0.035 mmol) was added and furtherdegassed for 5 min. The resulting mixture was heated to reflux for 16 hunder Ar. Reaction mass was filtered through celite and the filtrate wasdiluted with water (50 mL) and the organic product was extracted withEtOAc (3×50 mL). The combined organic extract was washed with brine (200mL), dried (anhydr. Na₂SO₄) and concentrated to get crude. The crudeproduct was purified by CC (0-35% EtOAc in PE) to give[cis-EN2]-3-cyclopropyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine(180 mg, 72%) as liquid.

¹H-NMR (600 MHz, [d₆]-DMSO): δ=8.83-8.84 (1H), 8.19-8.24 (2H), 8.08(1H), 7.97-7.99 (1H), 7.79 (1H), 5.13-5.16 (1H), 4.01-4.04 (1H),3.78-3.82 (1H), 3.31 (3H), 2.62-2.67 (1H), 2.26-2.31 (1H), 2.13-2.18(1H), 1-70-1.73 (1H), 1.48-1.53 (4H), 1.01-1.07 (2H), 0.86-0.91 (1H),0.72-0.76 (1H).

[cis-EN2] SC-271—analytical chiral SFC: Chiralcel OH-H (250×4.6 mm 5μ),0.5% DEA in MeOH 10%, 3 g/min, Ret. Time 5.6; ee>95%

Synthesis of Thiophenols 3-(difluoromethyl)benzenethiol

Step 1: 1-(difluoromethyl)-3-iodobenzene

DAST (27 mL, 172.41 mmol) was added to a solution of 3-lodo benzaldehyde(10 g, 43.10 mmol) in DCM (150 mL) at 0° C. over a period of 10 min. TheRM was warmed to RT and stirred for 19 h. The RM was carefully quenchedinto ice water and extracted with DCM (2×150 mL). The combined organiclayer was washed with sat. NaHCO₃ solution, water (100 mL), brine (100mL), dried over Na₂SO₄ and concentrated to get crude. The crude compoundwas purified by CC (0-5% EtOAc in PE) to obtain 9.0 g (82.5%) of1-(difluoromethyl)-3-iodobenzene as yellow oil.

Step 2: 1,2-bis(3-(difluoromethyl)phenyl)disulfane

Sulphur powder (3.8 g, 118.11 mmol) was added to a suspension of1-(difluoromethyl)-3-iodobenzene (10 g, 39.37 mmol), Copper (I) iodide(750 mg, 3.93 mmol) and K₂CO₃(16.29 g, 118.11 m·mol) in DMF (100 mL) andstirred at 90° C. for 9 h. The RM was cooled to RT and filtered, washedthe cake with EtOAc (100 mL). The filtrate was washed with water (100mL), brine (100 mL), dried (Na₂SO₄) and concentrated to get 8 g1,2-bis(3-(difluoromethyl)phenyl)disulfane of crude. The crude was usedas such for the next step without purification.

Step 3: 3-(difluoromethyl)benzenethiol

Triphenylphosphine (17.36 g, 66.03 mmol) was added to a solution of61-1-B (7 g, 22.01 mmol) in toluene (70 mL), added 5 mL of Conc. HCl andstirred for 12 h at 700 C-800 C. The RM was cooled to RT and taken fornext step without isolation.

3-(difluoromethyl)benzenethiol

Step 1: 1-bromo-3-(difluoromethyl)-5-fluorobenzene

DAST (39 mL, 295.56 mmol) was added to a solution of3-bromo-5-fluorobenzaldehyde (15 g, 73.89 mmol) in DCM (150 mL) at −78°C. over a period of 10 min. The RM was warmed to RT and stirred for 19h. The RM was carefully quenched into ice water and extracted withDCM(2×250 mL). The combined organic layer was washed with sat. NaHCO₃solution, water (150 mL), brine (150 mL), dried over Na₂SO₄ andconcentrated to get crude. The crude compound was purified by CC (0-5%EtOAc in PE) to obtain 10.0 g (60.6%) of1-bromo-3-(difluoromethyl)-5-fluorobenzene as low boiling light yellowoil.

Step 2: (3-(difluoromethyl)-5-fluorophenyl)(4-methoxybenzyl)sulfan

To a Ar purged solution of DIPEA (15.2 mL, 85.20 mmol) in 1,4-dioxane(100 mL) was added Pd₂(dba)₃ (1.17 g, 1.27 mmol), Xantphos (1.7 g, 2.98mmol), (4-methoxyphenyl)methanethiol (6.7 mL, 46.86 mmol) and1-bromo-3-(difluoromethyl)-5-fluorobenzene (9.5 g, 42.60 mmol). Thereaction was heated to 90° C. for 2 h. The RM was cooled to RT andfiltered, washed the filter cake with EtOAc (100 mL). The filtrate waswashed with water (100 mL), brine (100 mL), dried (Na₂SO₄) andconcentrated to get the crude compound. The crude compound was purifiedby CC (0-5% EtOAc in PE) to obtain 9.0 g (74%) of(3-(difluoromethyl)-5-fluorophenyl)(4-methoxybenzyl)sulfan as a lightyellow oil.

Step 3: 3-(difluoromethyl)-5-fluorobenzenethiol

Trifluoroacetic acid (36.0 mL) was added to a clear solution of(3-(difluoromethyl)-5-fluorophenyl)(4-methoxybenzyl)sulfan (9.0 g, 33.08mmol) in anisole (18.0 mL) at RT. The reaction was heated to 80° C. for1 h, then the RM was cooled to RT and quenched in ice water andextracted with EtOAc (2×150 mL). The combined organic layer was washedwith 5N NaOH solution (3×300 mL). the combined aq. layer was acidifiedwith 2NHCl solution up to pH=2.0 and extracted with dichloromethane(2×200 mL), the combine organic layer was washed with water (100 mL),sat. NaHCO₃ (100 mmL) followed by brine (100 mL), dried (Na₂SO₄) andconcentrated to obtain 5.0 g (86.2%) of3-(difluoro-methyl)-5-fluorobenzenethiol as a colorless oil.

Synthesis of Examples 61 to 77 SC-330 to SC-356 General Reaction Schemefor Examples SC-330, SC-331, SC-336 to SC-338, SC-353 & SC-354

Dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine(Example 61)

Step 5:Dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine

A suspension of 2M HNMe₂ in THF (969 μL, 1.94 mmol) and [cis-rac]2-bromo-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-337 (300 mg, 0.646 mmol) [see step 4 Example 64] was stirred in aclosed vessel at 100° C. over the weekend. The RM was concentrated andsat. aq. Na₂CO₃ and EtOAc (75 mL) were added. The organic layer wasseparated, washed with brine, dried (Na₂SO₄) and concentrated.Purification by flash chromatography (silica, gradient heptane/EtOAc,9:1 to 0:1) gave [cis-rac]dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine(125 mg, 45%). This reaction was repeated on the same scale and gaveextra [cis-rac]dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine(45 mg, 16%).

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine:δ 8.14 (s, 1H), 8.08-7.99 (m, 2H), 7.94 (d, J=7.8 Hz, 1H), 7.73 (t,J=7.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 6.51 (d, J=8.8 Hz, 1H),4.32 (dd, J=11.5, 2.0 Hz, 1H), 4.17-4.08 (m, 1H), 3.70 (td, J=12.3, 2.1Hz, 1H), 3.08 (s, 6H), 2.34 (td, J=12.8, 5.4 Hz, 1H), 2.23 (t, J=12.3Hz, 1H), 1.65 (dt, J=13.0, 2.2 Hz, 1H), 1.61-1.48 (m, 5H+H₂O). Therelative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis-rac]dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine

[Cis-rac]dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine(170 mg, 0.397 mmol) was subjected to preparative chiral-LC (IC-column,heptane/EtOH, 70:30). The products were dissolved in MeOH and slowlyevaporated by air to form crystals, which were washed with pentane (2×)and dried on filter for 2 h to give [cis-EN1] SC-330 (62 mg, 36%) and[cis-EN2] SC-331 (73 mg, 42%).

[cis-EN1] SC-330—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 70/30, Ret. Time 9.739; ee>95%

[cis-EN2] SC-331—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 70/30, Ret. Time 20.471; ee>95%

2,6-Dimethyl-3-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 63)

See step 3 Example 15. Cis/trans mixture (1:4).

2-Methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 64) and2-Bromo-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 65)

Step 1: 2-(6-Bromopyridin-3-yl)tetrahydro-2H-pyran-4-yl methanesulfonate

To an ice-cooled solution of 6-bromonicotinaldehyde (5.32 g, 28.6 mmol)in DCM (30 mL) was dropwise added MsOH (18.6 mL, 286 mmol), followed bythe dropwise addition of 3-buten-1-ol (2.46 mL, 28.6 mmol). The reactionwas stirred at 0° C. for 2 h and then basified with sat. aq. Na₂CO₃ andH₂O (1/1, v/v). The RM was extracted with DCM, dried (Na₂SO₄) andconcentrated. Crystallisation from EtOAc/heptane gave the first crop ofthe desired product (4.787 g). The mother liquor was concentrated andthe resulting residue was crystallised from EtOAc/heptane to give thesecond crop of the desired product (2.575 g). All the crystals werecombined to yield 2-(6-bromopyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (7.362 g, 77%).

Step 2:2-Bromo-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

A mixture of Cs₂CO₃ (6.92 g, 21.2 mmol), 3-(trifluoromethyl)benzenethiol(3.39 mL, 25.5 mmol) and 2-(6-bromopyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (7.14 g, 21.2 mmol) in anhydr. MeCN (70 mL) was stirredat 40° C. overnight. The RM was allowed to cool to RT, filtered overCelite and eluted with MeCN. The filtrate was concentrated and subjectedto flash chromatography (silica, gradient heptane/EtOAc, 97:3 to 7:3) togive 5.0 g of impure title compound, which was used as such in the nextstep.

Step 3:2-Bromo-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

Oxone (12.56 g, min. 35.4 mmol) was added to a suspension of crude2-bromo-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(4.93 g, max. 11.8 mmol) in MeCN (40 mL) and H₂O (40 mL). The RM wasstirred overnight at RT and then concentrated a bit. EtOAc (300 mL) wasadded and sat. aq. NaHCO₃ and sat. aq. Na₂CO₃ (1/1, v/v) was added untilbasic. The organic layer was separated, washed with brine, dried(Na₂SO₄) and concentrated. The residue was purified by flashchromatography (silica, gradient heptane/EtOAc, 85:15→1:1) to give thedesired compound (4.56 g, 46% (corrected for residual solvent) over 2steps).

Step 4:2-Bromo-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

A solution of 1.7M KOt-Bu in THF (6.63 mL, 11.3 mmol) was dropwise addedto a solution of2-bromo-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(4.23 g, 8.92 mmol (corrected for residual solvent)) in dry THF (40 mL)and dry DMF (20 mL) while cooling with an acetone/dry ice bath and theRM was stirred for 15 min. To the cooled solution was dropwise added Mel(1.76 mL, 28.2 mmol) and the RM was stirred for 1.5 h. The cooling bathwas removed and ice-cold H₂O (150 mL) was added. The resulting mixturewas stirred for 15 min and filtered. The residue was washed with H₂O anddried on the filter for 30 min. Crystallisation from MeOH gave desired[cis-rac]2-bromo-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-337 (2.52 g, 61%).

Step 5:5-(4-Methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-2-(methylthio)pyridine

To a suspension of NaSMe (453 mg, 6.46 mmol) in pyridine (5.2 mL) wasadded [cis-rac]2-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridineSC-337 (750 mg, 1.62 mmol) and the RM was stirred at 60° C. overnight.The RM was allowed to cool to RT, poured into ice-water (50 mL) andextracted with EtOAc (100 mL). The organic layer was washed with brine,dried (Na₂SO₄) and concentrated. Crystallisation from MeOH gave thefirst crop of the title compound (443 mg). The mother liquor wasconcentrated and crystallisation from MeOH of this residue gave thesecond crop of the title compound (127 mg). The crystals were combinedto yield [cis-rac]5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-2-(methylthio)pyridine(570 mg, 82%).

Step 6:2-Methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

Oxone (742 mg, min. 2.09 mmol) was added to a solution of [cis-rac]5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-2-(methylthio)pyridine(300 mg, 0.695 mmol) in MeCN (3 mL), THF (1.5 mL) and H₂O (1.5 mL) andthe resulting RM was stirred overnight at RT and then concentrated abit. H₂O was added and the resulting precipitate was filtered off,washed with H₂O (2×) and dried on a filter overnight. Purification byflash chromatography (silica, gradient heptane/EtOAc, 9:1→0:1) yielded[cis-rac]2-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(187 mg, 58%).

¹H NMR (400 MHz, CDCl₃) of [cis-rac]2-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine:δ 8.64 (s, 1H), 8.13 (s, 1H), 8.09 (d, J=8.1 Hz, 1H), 8.04 (d, J=7.8 Hz,1H), 8.00-7.91 (m, 2H), 7.76 (t, J=7.8 Hz, 1H), 4.60 (d, J=11.5 Hz, 1H),4.22 (dd, J=12.1, 5.1 Hz, 1H), 4.12 (q, J=7.0 Hz, 0.2H, EtOAc), 3.73(td, J=12.5, 2.0 Hz, 1H), 3.24 (s, 3H), 2.39 (td, J=12.9, 5.4 Hz, 1H),2.14 (t, J=12.3 Hz, 1H), 2.05 (s, 0.3H, EtOAc), 1.81 (d, J=13.0 Hz, 1H),1.59 (s, 3H), 1.59-1.56 (m, 3H+H₂O), 1.26 (t, J=7.1 Hz, 0.3H, EtOAc).

The relative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis-rac]2-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

[Cis-rac]2-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(187 mg, 0.403 mmol) was subjected to preparative chiral-LC (IC-column,heptane/EtOH, 70:30). The products were dissolved in MeOH and slowlyevaporated by air to form crystals, which were washed with MeOH (2×) anddried on filter for 2 h to give [cis-EN1] SC-336 (62 mg, 33%) and[cis-EN2] SC-338 (60 mg, 32%).

[cis-EN1] SC-336—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 70/30, Ret. Time 38.834; ee>95%

[cis-EN2] SC-338—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 70/30, Ret. Time 44.234; ee>95%

2-Isopropoxy-5-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 67)

See step 3 Example 9. Cis/trans mixture (1:9).

[Trans-rac]2-methyl-6-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 69)

See step 3 Example 15.

2-(Trifluoromethyl)-5-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 70)

See step 3 Example 14. Cis/trans mixture (3:7).

General Reaction Scheme for Examples 62, 71 to 75 (SC-332 to SC-334,SC-343 to SC-348 to SC-352)

2-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine(Example 62)

Step 4:2-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine

A solution of2-cyclopropyl-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyrazine(step 3, Example 18) (3.00 g, 7.27 mmol) in dry THF (35 mL) wasprepared, the temperature was lowered to −78° C., 1 M KOtBu in THF(21.82 mL, 21.82 mmol) was added dropwise and the RM was stirred for 10min. Dropwise addition of Etl (2.91 mL, 36.4 mmol) was followed bystirring the RM at −78° C. for 1 h. The flask was left in the coolingbath. Consequently, the temperature was kept at −78° C. for a few hours,followed by slow raise of temperature to RT and stirring overnight atRT. The RM was combined with aq. 1 M KHSO₄ (200 mL), H₂O (50 mL) andEtOAc (250 mL) to result in a two phase system. The layers wereseparated, the aq. layer was extracted with EtOAc (50 mL). Thecombination of organic layers was washed with aq. 1 M Na₂S₂O₃ (2×50 mL),sat. aq. NaHCO₃ (50 mL) and dried (brine and Na₂SO₄), followed byconcentration. The residue was dissolved in DCM (5 mL), addition ofi-PrOH (50 mL) was followed by concentration. The residue was used for afew crystallisation-cycles from hot i-PrOH. The crystals were filteredoff, washed with i-PrOH and dried by suction to provide [cis-rac]2-cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine(1.01 g, 31%).

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]2-cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine:δ 8.45 (m, 1H), 8.37 (d, J=1.3 Hz, 1H), 8.12 (s, 1H), 8.04 (d, J=7.9 Hz,1H), 7.94 (d, J=7.8 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 4.54 (dd, J=11.3,2.2 Hz, 1H), 4.17 (dd, J=12.0, 4.0 Hz, 1H), 3.72 (td, J=12.3, 2.0 Hz,1H), 2.28-1.99 (m, 6H), 1.83-1.74 (m, 1H), 1.19 (t, J=7.5 Hz, 3H),1.11-1.02 (m, 4H).

A filtrate from a crystallisation cycle described above wasconcentrated, dissolved in DCM (0.5 mL) and used for flashchromatography (silica, gradient heptane/EtOAc, 95:5 to 9:1). Theproduct was dissolved in MeCN (5 mL) and concentrated. The residue wasdissolved in MeCN (2 mL), addition of H₂O (2 mL) was followed by freezedrying to result in [trans-rac]2-cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazineSC-333 (45 mg, 1%).

¹H-NMR (400 MHz, CDCl₃) of [trans-rac]2-cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazineSC-333: δ 8.52 (s, 1H), 8.42 (d, J=1.4 Hz, 1H), 8.19 (s, 1H), 8.13 (d,J=7.9 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.77 (t, J=7.8 Hz, 1H), 5.42 (dd,J=11.7, 2.4 Hz, 1H), 4.51 (td, J=12.2, 2.7 Hz, 1H), 4.11 (dd, J=11.7,5.5 Hz, 1H), 2.34 (d, J=15.4 Hz, 1H), 2.17 (d, J=15.1 Hz, 1H), 2.12-1.90(m, 3H), 1.67-1.54 (m, 6H+H₂O), 1.53-1.43 (m, 1H), 1.25 (s, 0.1H(impurity)), 1.23-1.17 (m, 0.2H (impurity)), 1.13-1.03 (m, 4H), 0.95 (t,J=7.4 Hz, 3H). The relative stereochemistry was assigned by comparingthe central ring signals in the ¹H-NMRs with the spectra of [cis-rac]and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis-rac]2-cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine

[Cis-rac]2-cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine(500 mg, 1.135 mmol) was subjected to preparative chiral-HPLC(IC-column, heptane/EtOH, 85:15). The two products were dissolved inEtOAc (20 mL), followed by concentration. The residues were dissolved inDCM (4 mL), followed by addition of silica (1 g) and concentration. Theresidues were brought on plugs of silica (3 g) and eluted with heptane(30 mL), the filtrates were discarded. Subsequently, elution with EtOAc(30 mL) provided two filtrates, which were concentrated. The productswere dissolved in MeCN (5 mL) and concentrated. The residues weredissolved in MeCN (2 mL), addition of H₂O (2 mL) was followed by freezedrying to result in 206 mg (41%) of

[cis-EN1] SC-332 and 204 mg (40%) of [cis-EN2] SC-334.

[cis-EN1] SC-332—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 80/20, Ret. Time 10.706; ee>95%

[cis-EN2] SC-334—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 80/20, Ret. Time 17.743; ee>95%

1-Methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-1H-pyrazole(Example 71)

Step 1:2-(1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

A solution of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carbaldehyde (2g, 10.67 mmol, purity 95%) and but-3-en-1-ol (0.936 mL, 10.88 mmol) inDCM (25 mL) was cooled to −16° C. using a NaCl/ice bath. MsOH (6.93 mL,107 mmol) was added at a slow rate, keeping the temperature below −10°C. The mixture was stirred at −16° C. for 30 min. The RM was slowlypoured out in a cooled solution of Na₂CO₃ (5.77 g, 54.4 mmol) in H₂O(100 mL). EtOAc/i-Pr₂O (1/1, v/v, 150 mL) was added and the mixture wasstirred vigorously for 30 min. The layers were separated and the organiclayer was washed with sat. aq. NaHCO₃ (2×50 mL) and brine (2×50 mL)before drying on Na₂SO₄ and concentration in vacuo. The product waspurified using flash chromatography (silica, gradient heptane/EtOAc, 1:1to 0:1) to give a colorless oil. The product was triturated with Et₂O togive the desired product (1.67 g, 47%) as a white solid. The motherliquor was concentrated in vacuo to give another batch of the desiredproduct (1.08 g, 30%) as a colorless oil; totaled yield 2.75 g (78%).

Step 2:1-Methyl-3-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A solution of2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (2.75 g, 8.38 mmol) in dry DMF (60 mL) was degassed byalternating vacuum and Ar 5 times with 1 min intervals. Cs₂CO₃ (6.82 g,20.94 mmol) and 3-(trifluoromethyl)benzenethiol (2.78 mL, 20.94 mmol)were added and the degassing sequence was repeated 3 times. The mixturewas stirred at 80° C. in a pre-heated oil bath under Ar for 2 h. Theheating was stopped and the mixture was stirred at RT for 16 h. The RMwas poured out in sat. aq. NaHCO₃ (50 mL) and the product was extractedwith EtOAc/i-Pr₂O (1/1, v/v, 2×125 mL). The combined organic layers werewashed with sat. aq. NaHCO₃ (2×50 mL) and brine (2×50 mL) before dryingon Na₂SO₄ and concentration in vacuo. The product was purified usingflash chromatography (silica, gradient heptane/EtOAc, 9:1 6:4) to givethe desired product (2.95 g, 85%).

Step 3:1-Methyl-3-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole

To a solution of1-methyl-3-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)-1H-pyrazole(2.85 g, 6.94 mmol) in MeOH (110 mL) was added a solution of oxone (6.40g, min. 18 mmol) in H₂O (80 mL) and the resulting white suspension wasstirred at RT for 2 h. The MeOH was distilled off in vacuo and theresidue was basified with sat. aq. NaHCO₃. The product was extractedwith i-Pr₂O/EtOAc (1/1, v/v, 250 mL). The organic layer was washed withsat. aq. NaHCO₃ (2×50 mL) and brine (2×50 mL) before drying on Na₂SO₄and concentration in vacuo. The product was purified using flashchromatography (silica, gradient heptane/EtOAc, 9:1 to 1:1, then flushwith EtOAc) to give the desired product (1.4 g, 45%) as a colorless oil.Also an impure batch (1.47 g) was obtained which was dissolved in MeOH(70 mL), cooled in an ice bath and a solution of oxone (229 mg, min.0.644 mmol) in H₂O (15 mL) was added, giving a white suspension. Themixture was stirred at RT for 3 h. More oxone (500 mg, min. 1.40 mmol)was added and the stirring was continued for 16 h. The MeOH was removedin vacuo and the residue was poured out in sat. aq. NaHCO₃ (50 mL). Theproduct was extracted with EtOAc (2×50 mL). The combined organic layerswere washed with sat. aq. NaHCO₃ (2×25 mL) and brine (2×25 mL) beforedrying on Na₂SO₄ and concentration in vacuo to give another batch of thedesired product (1.33 g, 43%) as a waxy solid; totaled yield 2.73 g(89%).

Step 4:1-Methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-1H-pyrazole

To a solution of1-methyl-3-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole(2.72 g, 6.15 mmol) in dry THF (40 mL) under Ar at −78° C. was added 1.7M KOtBu in THF (7.96 mL, 13.53 mmol) in a dropwise manner, keeping thetemperature below −70° C. The mixture was stirred at −78° C. for 10 min.Mel (1.531 mL, 24.59 mmol) was added dropwise, keeping the temperaturebelow −70° C. The mixture was stirred at −78° C. for 1 h. The coolingbath was removed and sat. aq. NaHCO₃ (50 mL) was added while still cold.The mixture was left to thaw and H₂O (50 mL) and EtOAc (100 mL) wereadded. The layers were separated and the aq. layer was extracted withEtOAc (50 mL). The combined organic layers were washed with sat. aq.NaHCO₃ (2×25 mL), aq. 1M Na₂S₂O₃ (2×25 mL) and brine (2×25 mL) beforedrying on Na₂SO₄ and concentration in vacuo. The product was dissolvedin DCM and left at RT for 16 h. The solid was filtered off and dried onair to give [cis-rac]1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-1H-pyrazole(1.65 g, 58%).

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-1H-pyrazole:6 8.17 (s, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.79 (t,J=7.8 Hz, 1H), 6.45 (s, 1H), 4.52 (dd, J=11.8, 2.0 Hz, 1H), 4.13 (dd,J=12.1, 4.2 Hz, 1H), 3.93 (s, 3H), 3.70 (td, J=12.4, 2.1 Hz, 1H), 2.44(t, J=12.3 Hz, 1H), 2.34 (td, J=12.9, 5.4 Hz, 1H), 1.92 (d, J=12.9 Hz,1H), 1.58-1.51 (m, 4.5H+H₂O).

The mother liquor was concentrated and purified using flashchromatography (silica, gradient heptane/EtOAc, 9:1 to 1:1) to give[trans-rac]1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-1H-pyrazoleSC-344 (197 mg, 7%) after trituration with pentane and drying in vacuo.

¹H-NMR (400 MHz, CDCl₃) of [trans-rac]1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-1H-pyrazoleSC-344: δ 8.14 (s, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H),7.79 (t, J=7.8 Hz, 1H), 6.44 (s, 1H), 5.35 (dd, J=11.9, 2.1 Hz, 1H),4.44 (td, J=12.7, 2.3 Hz, 1H), 4.08-3.96 (m, 4H), 2.62 (d, J=15.1 Hz,1H), 2.25 (d, J=15.4 Hz, 1H), 1.97-1.77 (m, 2H), 1.29 (s, 3H).

Another batch of [cis-rac]1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-1H-pyrazole(340 mg, 12%) was also obtained. The relative stereochemistry wasassigned by comparing the central ring signals in the ¹H-NMRs with thespectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis-rac]1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-1H-pyrazole

[Cis-rac]1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-1H-pyrazole(500 mg, 1.096 mmol) was subjected to preparative chiral LC (IC-column,heptane/EtOH, 95:5) to give 112 mg (22%) of [cis-EN1] SC-343 and 132 mg(26%) of [cis-EN2] SC-345.

[cis-EN1] SC-343—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/iPrOH 95/5, Ret. Time 12.420; ee>95%

[cis-EN2] SC-345—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/iPrOH 95/5, Ret. Time 15.937; ee>95%

2-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 72)

Step 1: 2-(6-Cyclopropylpyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

To a cooled (0° C.) solution of 6-cyclopropylnicotinaldehyde (0.98 g,6.66 mmol) and but-3-en-1-ol (0.573 mL, 6.66 mmol) in DCM (10 mL), MsOH(4.32 mL, 66.6 mmol) was added and the RM was stirred at RT for 72 h.The RM was combined with a RM which was prepared in the same manner from20 mg (0.14 mmol) of 6-cyclopropylnicotinaldehyde. The combined RMs werediluted with DCM (50 mL) and basified using sat. aq. NaHCO₃ (˜100 mL)until basic. The aq. phase was extracted with DCM (50 mL) and thecombined organics were dried over Na₂SO₄. The solvent was removed underreduced pressure and the product was purified using flash chromatography(silica, gradient DCM/(10% MeOH in DCM), 1:0 to 1:1) to give 2.6 g(‘129%’) of the desired product.

Step 2:2-Cyclopropyl-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

K₂CO₃ (2.417 g, 17.49 mmol) was added to a solution of2-(6-yclopropylpyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate(2.6 g, max. 6.66 mmol) and 3-(trifluoromethyl)benzenethiol (2.325 mL,17.49 mmol) in MeCN (80 mL) under N₂. The RM was stirred at 50° C. for18 h. More 3-(trifluoromethyl)benzenethiol (2.325 mL, 17.49 mmol) andK₂CO₃ (2.417 g, 17.49 mmol) were added and the RM was stirred for 5 h at50° C. The RM was concentrated under reduced pressure and the residuewas partitioned between DCM (50 mL) and H₂O (50 mL). The aq. phase wasextracted with DCM (2×50 mL). The combined organics were dried overNa₂SO₄ and concentrated under reduced pressure to give a brown oil. Theproduct was coated on silica and purified using flash chromatography(silica, gradient heptane/i-Pr₂O, 1:0 to 0:1) to give a pure and animpure batch of the desired product. The impure batch was purifiedfurther using flash chromatography (silica, gradient heptane/acetone,1:0 to 7:3). Both batches were combined to afford the title compound(1.03 g, 40% over two steps).

Step 3:2-Cyclopropyl-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

A solution of oxone (1.57 g, min. 4.4 mmol) in H₂O (20 mL) was addeddropwise to a cooled (0° C.) solution of2-cyclopropyl-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(970 mg, 2.56 mmol) in MeOH (25 mL). The pale yellow suspension wasstirred for 2 h at RT. More oxone (236 mg, min. 0.66 mmol) was added andthe RM was stirred at RT for 18 h. The RM was combined with a RM whichwas prepared in the same manner from 61 mg (0.16 mmol) of2-cyclopropyl-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridineand the solvent, with the exception of H₂O, was removed under reducedpressure. The residue was partitioned between H₂O (50 mL), sat. aq.NaHCO₃ (50 mL) and EtOAc (100 mL). The aq. phase was extracted withEtOAc (50 mL). The combined organics were washed with brine and driedover Na₂SO₄. The solvent was removed under reduced pressure. The productwas purified using flash chromatography (silica, gradient heptane/EtOAc,1:0 to 1:1) and co-evaporated with heptane (50 mL) to give 0.95 g (85%)of the desired product.

Step 4:2-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

1.7 M KOtBu in THF (1.930 mL, 3.28 mmol) was added dropwise via asyringe to a cooled (−78° C., acetone/dry ice) solution of2-cyclopropyl-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(900 mg, 2.187 mmol) in dry THF (15 mL) under N₂ resulting in an orangesolution. After stirring for 30 min at −78° C., Mel (0.684 mL, 10.94mmol) was added dropwise by syringe and the RM was stirred for 30 min.The RM was quenched with half sat. aq. NH₄Cl (10 mL) and combined with aRM which was prepared in the same manner starting from 50 mg (0.12 mmol)of2-cyclopropyl-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine.The RM was partitioned between sat. aq. NaHCO₃ (50 mL) and EtOAc (50mL). The aq. layer was extracted with EtOAc (50 mL) and the combinedorganics were washed with aq. 1 M Na₂S₂O₃ (50 mL), brine (50 mL), dried(Na₂SO₄) and evaporated to dryness. The product was purified using flashchromatography (silica, gradient heptane/EtOAc, 1:0 to 1:1) to afford0.82 g (83%) of [cis-rac]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineand 94 mg (10%) of [trans-rac]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-347.

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine:δ 8.31 (d, J=2.1 Hz, 1H), 8.13 (s, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.95 (d,J=7.8 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.53 (dd, J=8.1, 2.3 Hz, 1H),7.12 (d, J=8.1 Hz, 1H), 4.42 (dd, J=11.5, 2.0 Hz, 1H), 4.21-4.11 (m,1H), 3.70 (td, J=12.4, 2.1 Hz, 1H), 2.36 (td, J=12.8, 5.3 Hz, 1H), 2.19(t, J=12.3 Hz, 1H), 2.03 (p, J=6.4 Hz, 1H), 1.75-1.50 (m, 5H), 1.30-1.23(m, 0.3H (heptane)), 0.99 (d, J=6.6 Hz, 4H), 0.88 (t, J=6.8 Hz, 0.1H(heptane)).

[Trans-rac]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-347 was lyophilised using MeCN/H₂O (3/1, v/v, 2 mL) to removeresidual solvent.

¹H-NMR (400 MHz, CDCl₃) of [trans-rac]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-347: δ 8.43 (d, J=2.1 Hz, 1H), 8.19-8.06 (m, 2H), 7.96 (d, J=7.8 Hz,1H), 7.77 (t, J=7.8 Hz, 1H), 7.54 (dd, J=8.1, 2.2 Hz, 1H), 7.11 (d,J=8.1 Hz, 1H), 5.21 (dd, J=11.7, 2.3 Hz, 1H), 4.41 (td, J=12.4, 2.5 Hz,1H), 4.08-4.00 (m, 1H), 2.43-2.35 (m, 1H), 2.34-2.25 (m, 1H), 2.07-1.98(m, 1H), 1.84 (ddd, J=15.4, 12.7, 5.7 Hz, 1H), 1.63 (dd, J=15.3, 11.8Hz, 1H), 1.23 (s, 3H), 1.03-0.94 (m, 4H).

The relative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis-rac]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-Pyran-2-yl]-pyridine

[Cis-rac]2-cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(300 mg, 0.705 mmol) was subjected to preparative chiral-LC (IC-column,heptane/EtOH 9:1). The products was transferred to shipment vials usingEtOH (5 mL) and co-evaporated with heptane (3×2 mL) to afford 135 mg(45%) of [cis-EN1] SC-346 and 135 mg (45%) of [cis-EN2] SC-348

[cis-EN1] SC-346—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 90/10, Ret. Time 16.511; ee>95%

[cis-EN2] SC-348—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 90/10, Ret. Time 23.574; ee>95%

2-(Trifluoromethyl)-6-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 74) and2-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-(trifluoromethyl)-pyridine(Example 75)

Step 1: 2-(6-(Trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

A solution of 6-(trifluoromethyl)picolinaldehyde (5.26 g, 30.0 mmol) andbut-3-en-1-ol (2.58 mL, 30.0 mmol) in DCM (50 mL) was cooled to 0° C.MsOH (19.51 mL, 300 mmol) was added dropwise and the RM was stirred atRT for 30 min. DCM (250 mL) was added followed by the careful additionof sat. aq. NaHCO₃ (500 mL). The organic layer was dried (Na₂SO₄) andevaporated under reduced pressure, to give 9.13 g (93%) of the desiredproduct.

Step 2:2-(Trifluoromethyl)-6-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

A solution of2-(6-(trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (5.04 g, 15.49 mmol) in dry MeCN (50 mL) was flushedwith N₂ for 30 min. K₂CO₃ (5.35 g, 38.7 mmol) was added followed by3-trifluoromethyl)benzenethiol (5.25 mL, 38.7 mmol). The RM was stirredat 50° C. overnight under N₂. The suspension was filtered over Celiteand the residue washed with EtOAc. The combined filtrate was evaporatedunder reduced pressure. The product was coated on silica and purified byflash chromatography (silica, gradient heptane/EtOAc, 1:0 to 3:1) toafford 4.58 g (73%) of pure title compound and 1.58 g of impure titlecompound. The impure batch was purified further by flash chromatography(silica, gradient heptane/EtOAc, 1:0 to 4:1), to afford another 0.82 g(13%) of pure title compound. Total yield: 5.40 g (86%).

Step 3:2-(Trifluoromethyl)-6-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

H₂O (25 mL) was added to oxone (11.56 g, 32.5 mmol) and the mixture wasstirred at RT for 15 min. The resulting suspension was added to asolution of2-(trifluoromethyl)-6-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(5.30 g, 13.01 mmol) in MeOH (25 mL). The RM was stirred at RTovernight. More MeOH (5 mL) was added followed by oxone (2.313 g, 6.51mmol) in H₂O (5 mL). Stirring was continued at RT overnight. Most of theMeOH was removed under reduced pressure. DCM (300 mL) and H₂O (200 mL)were added. The aq. layer was extracted with DCM (200 mL). Organiclayers were combined, dried (Na₂SO₄) and evaporated under reducedpressure. The product was purified by flash chromatography (silica,gradient heptane/EtOAc, 1:0 to 2:1), to afford 5.37 g (94%) of thedesired product SC-350 (cis/trans mixture (1:4)).

Step 4:2-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-(trifluoromethyl)-pyridine

This reaction was carried out under Ar. The reaction vial was dried(heat-gun) before use. A solution of2-(Trifluoromethyl)-6-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-350 (1.19 g, 2.71 mmol) in dry THF (15 mL) was cooled to −78° C., 1 MLiHMDS in THF (4.06 mL, 4.06 mmol) was added dropwise, 10 min later Mel(0.339 mL, 5.42 mmol) was added dropwise and stirring was continued at−78° C. for 6 h and the RM was allowed to very slowly warm to RTovernight. Half sat. aq. NH₄Cl (50 mL) and DCM (50 mL) were added. Theaq. layer was extracted with DCM (50 mL). Organic layers were combined,washed with aq. 1 M Na₂S₂O₃, dried (Na₂SO₄) and evaporated to dryness.The product was purified by flash chromatography (silica, gradientheptane/EtOAc, 9:1 to 2:1) to give 0.79 g (64%) of [cis-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-(trifluoromethyl)-pyridineSC-351 and 156 mg (13%) of [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-(trifluoromethyl)-pyridineSC-352.

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-(trifluoromethyl)-pyridineSC-351: δ 8.12 (s, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H),7.90 (t, J=7.9 Hz, 1H), 7.78-7.69 (m, 2H), 7.60 (d, J=7.7 Hz, 1H), 4.60(dd, J=9.1, 5.0 Hz, 1H), 4.23 (dd, J=12.1, 4.3 Hz, 1H), 3.76 (td,J=12.3, 2.1 Hz, 1H), 2.40 (td, J=12.9, 5.5 Hz, 1H), 2.15-2.03 (m, 2H),1.64-1.52 (m, 7.6H+H₂O).

¹H-NMR (400 MHz, CDCl₃) of [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-(trifluoromethyl)-pyridineSC-352: δ 8.24-8.20 (m, 2H), 7.97 (d, J=7.7 Hz, 1H), 7.88 (t, J=7.8 Hz,1H), 7.80 (t, J=8.1 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.57 (d, J=7.7 Hz,1H), 5.43 (dd, J=11.4, 2.3 Hz, 1H), 4.47 (td, J=12.2, 2.6 Hz, 1H),4.15-4.04 (m, 1.1H+EtOAc), 2.67-2.47 (m, 2H), 2.05 (s, 0.1H (EtOAc)),1.85 (ddd, J=15.3, 12.5, 5.7 Hz, 1H), 1.66 (dd, J=15.4, 11.4 Hz, 1H),1.28-1.25 (m, 0.4H (impurity)), 1.23 (s, 3H), 0.88 (t, J=6.7 Hz, 0.1H(EtOAc)).

The relative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 76)

Step 5:2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

[Cis-rac]2-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridineSC-337 (300 mg, 0.646 mmol) [see step 4, Example 64] was added to asolution of 5.4 M NaOMe in MeOH (239 μL, 1.29 mmol) and pyridine (1.05mL). The RM was stirred at 60° C. over the weekend, allowed to cool toRT and poured into ice-water (50 mL). After the addition of EtOAc (75mL), the organic layer was separated. The organic layer was washed withbrine, dried (Na₂SO₄) and concentrated. Crystallisation from MeOH gavethe title compound (154 mg). The mother liquor was concentrated andcrystallisation (MeOH) of this residue gave extra title compound (18mg). The crystals were combined to give a total amount of 172 mg (64%)of [cis-rac]2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine.

¹H-NMR (400 MHz, CDCl₃) of [cis-rac]2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine:δ 8.14 (s, 1H), 8.08-8.02 (m, 2H), 7.95 (d, J=7.8 Hz, 1H), 7.74 (t,J=7.9 Hz, 1H), 7.58 (dd, J=8.6, 2.4 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H),4.40 (dd, J=11.6, 2.0 Hz, 1H), 4.15 (dd, J=12.0, 4.1 Hz, 1H), 3.93 (s,3H), 3.71 (td, J=12.4, 2.2 Hz, 1H), 3.49 (d, J=5.4 Hz, 0.1H (MeOH)),2.36 (td, J=12.8, 5.4 Hz, 1H), 2.21 (t, J=12.3 Hz, 1H), 1.74-1.66 (m,1H), 1.59-1.50 (m, 5.3H+H₂O).

The relative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis-rac]2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

[Cis-rac]2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(170 mg, 0.409 mmol) was subjected to preparative chiral-LC (IC-column,heptane/EtOH, 90:10). The products were dissolved in MeOH and slowlyevaporated by air to form crystals, which were washed with MeOH (2×) anddried on filter for 2 h to give [cis-EN1] SC-353 (61 mg, 35%) and[cis-EN2] SC-354 (56 mg, 33%).

[cis-EN1] SC-353—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 90/10, Ret. Time 12.878; ee>95%

[cis-EN2] SC-354—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 70/30, Ret. Time 17.389; ee>95%

General Reaction Scheme for Examples 68 and 77 (SC-340, SC-355 & 356)

3-Chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)pyridine(Example 68) and3-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(Example 77)

Step 1:2-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

To a solution of 3-chloro-5-(trifluoromethyl)picolinaldehyde (4.64 g,22.1 mmol) and MsOH (14.4 mL, 221 mmol) in DCM (25 mL) was added3-buten-1-ol (1.91 mL, 22.1 mmol). The RM was stirred at 40° C.overnight. The RM was allowed to cool to RT, quenched with sat. aq.Na₂CO₃, extracted with DCM and concentrated. The residue was purified byflash chromatography (silica, gradient heptane/EtOAc, 97:3 to 3:7)resulting in the title compound (5.27 g, 66%).

Step 2:3-Chloro-5-(trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

A suspension of Cs₂CO₃ (4.77 g, 14.7 mmol) and2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (5.27 g, 14.8 mmol) in dry MeCN (50 mL) was bubbledthrough with N₂ for 5 min and 3-trifluoromethyl)benzenethiol (2.34 mL,17.6 mmol) was added. The RM was stirred at 40° C. overnight. The RM wasallowed to reach RT, filtered over Celite, eluted with MeCN andconcentrated. The residue was dissolved in EtOAc (400 mL), washed withsat. aq. Na₂CO₃, brine, dried (Na₂SO₄) and concentrated. The residue waspurified by flash chromatography (silica, gradient heptane/EtOAc, 97:3to 70:30) to yield the desired product (4.97 g, 77%).

Step 3:3-Chloro-5-(trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

Oxone (9.60 g, 27.0 mmol) was added to a milky suspension of3-chloro-5-(trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(4.97 g, 11.3 mmol) in MeCN (30 mL) and H₂O (30.0 mL). The RM wasstirred at RT overnight and concentrated a bit. EtOAc (250 mL) and asolution of sat. aq. NaHCO₃ and sat. aq. Na₂CO₃ (1/1, v/v) was added tothe RM. The organic layer was separated, washed with brine, dried(Na₂SO₄), concentrated and co-evaporated with Et₂O (twice) to give thedesired product (4.84 g, 91%).

Step 4:3-Chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)pyridine

A solution of 1M LiHMDS in THF (15 mL, 15 mmol) was dropwise added to asolution of3-chloro-5-(trifluoromethyl)-2-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(4.11 g, 8.67 mmol) in dry THF (50 mL) while cooling with an acetone/dryice bath. The RM was stirred at −78° C. for 15 min and Mel (1.1 mL, 18mmol) was dropwise added. The RM was allowed to very slowly warm to RTovernight. The RM was poured into ice-water and stirred for 15 min. Theprecipitate was filtered and washed with H₂O (2×). The residue wasdissolved in DCM and the organic layer was separated with a phaseseparator and concentrated. Crystallization of the residue from MeOHgave [cis-rac]3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)pyridineSC-340 (Example 68, 1.623 g, 35%).

Step 5:2-(4-Methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)pyridine

[Cis-rac]3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)pyridineSC-340 (750 mg, 1.41 mmol) was added to a suspension of MeSNa (431 mg,6.15 mmol) in pyridine (5 mL). The RM was stirred at 60° C. overnightand then allowed to reach RT. The RM was poured into ice-water (50 mL)and extracted with EtOAc (75 mL). The organic layer was washed withbrine, dried (Na₂SO₄) and concentrated. Crystallization of the residuefrom MeOH gave the desired product (609 mg, 80%).

Step 6:3-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine

Oxone (641 mg, 1.80 mmol) was added to a solution of2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-5-(trifluoromethyl)pyridine(300 mg, 0.559 mmol) in MeCN (3 mL), THF (1.5 mL) and H₂O (1.5 mL) andthe resulting RM was stirred at 40° C. overnight and then concentrated abit. To the RM was added H₂O and the resulting precipitate wasfiltrated, washed with H₂O (2×) and dried on a filter overnight.Purification by flash chromatography (silica, gradient heptane/EtOAc,9:1 to 0:1) yielded [cis-rac]3-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(207 mg, 70%).

¹H NMR (400 MHz, CDCl₃) of [cis-rac]3-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine:6 9.06 (s, 1H), 8.61 (d, J=1.7 Hz, 1H), 8.20 (s, 1H), 8.13 (d, J=7.9 Hz,1H), 7.96 (d, J=7.8 Hz, 1H), 7.77 (t, J=7.8 Hz, 1H), 5.46 (dd, J=11.3,1.8 Hz, 1H), 4.16 (dd, J=11.3, 4.9 Hz, 1H), 3.86 (td, J=12.5, 2.1 Hz,1H), 3.26 (s, 3H), 2.83-2.73 (m, 1H), 2.38 (td, J=13.0, 5.3 Hz, 1H),2.05 (s, 0.1H (impurity)), 1.96 (d, J=13.3 Hz, 1H), 1.66 (d, J=13.2 Hz,1H), 1.59 (s, 3H), 1.29-1.20 (m, 0.2H (aliphatic impurity).

The relative stereochemistry was assigned by comparing the central ringsignals in the ¹H-NMRs with the spectra of [cis-rac] and [trans-rac]2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine.

Chiral resolution of [cis-rac]3-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine

[Cis-rac]3-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine(202 mg, 0.380 mmol) was subjected to preparative chiral-LC (IC-column,heptane/EtOH, 80:20). The products were dissolved in MeOH and slowlyevaporated by air to form crystals, which were washed with MeOH (2×) anddried on filter for 2 h to give [cis-EN1] SC-355 (68 mg, 34%) and[cis-EN2] SC-356 (73 mg, 36%).

[cis-EN1] SC-355—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 80/20, Ret. Time 9.705; ee>95%/specificrotation [α]_(D) ^(27.3) −0.26° (c 0.78; DCM).

the relative stereochemistry was confirmed by 2D-NMR. A NOE was observedfor the sulfone aromate with H1_(ax) en H5_(ax) and also a NOE wasobserved for the Me-group with H4_(ax). Ent1

[cis-EN2] SC-356—analytical chiral HPLC: chiralpak IC (250×4.6 mm 5μ), 1ml/min, 35° C., heptane/EtOH 80/20, Ret. Time 15.643; ee>95%/specificrotation [α]_(D) ^(27.6) +1.34° (c 0.82; DCM).

Synthesis of Examples 78 to 96 (SC-400 to SC-454) Cis/Trans Assignmentof SC-400 to SC-454

The cis racemic [cis-rac] and trans racemic [trans-rac] compounds wereseparated after the methylation step using CC or prep-HPLC. Theassignment of cis racemic [cis-rac] versus trans racemic [trans-rac] wascarried out by NOE studies. In some cases only the cis racemic [cis-rac]compound was assigned by NOE studies at this stage (after themethylation step). In these cases the trans racemic [trans-rac] compoundwas confirmed by NOE studies on the final trans racemic [trans-rac]target molecule. Formation of the cis racemic [cis-rac] isomer isgenerally favoured over formation of the trans racemic [trans-rac]isomer (generally yield<10%).

5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-pyrrolidin-1-yl-pyridine(Example 78)

Step 1: 2-(6-Chloropyridin-3-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

To a solution of 6-chloronicotinaldehyde (8 g, 56.7 mmol, 1 eq) in DCM(80 ml) was added methane sulfonic acid (36.7 ml, 567 mmol, 10 eq) at 0°C. and the RM was stirred for 10 min. Then 3-buten-1-ol (4.0 g, 56.7mmol, 1 eq) was added and the RM was stirred at RT for 2 h. The RM wasquenched with ice-water (100 ml) and basified to pH=10 using sat. NaHCO₃solution. The aq. layer was extracted with DCM (2×250 ml). The combinedorganic layers were washed with brine (100 ml), dried (Na₂SO₄) andconcentrated afforded the desired product (12 g, 72%).

Step 2:2-Chloro-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

To a solution of 3-(trifluoromethyl)benzenethiol (8.8 g, 49.48 mmol, 1.2eq) in DMF (150 ml), was added K₂CO₃ (17.06 g, 123.6 mmol, 3 eq) and2-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-yl methanesulfonate in DMF(12 g, 41.23 mmol, 1 eq) and the RM was heated to 50° C. and stirred for18 h. After completion of the reaction, the mixture was diluted withEtOAc (2×250 ml), washed with water (2×250 ml) and brine (200 ml), dried(Na₂SO₄) and concentrated in vacuum to provide the crude compound whichwas purified by CC (silica-gel; 15-20% EtOAc in PE) to afford thedesired product (10 g, 65%).

Step 3:2-Chloro-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

Oxone (49.38 g, 80.42 mmol, 3 eq) in water (50 ml,) was added to asolution of2-chloro-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(10 g, 26.80 mmol, 1 eq) in EtOH (100 mL) at RT and the RM was stirredfor 14 h. After completion of the reaction, EtOH was distilled off underreduced pressure. The residue was diluted with water (100 ml) andextracted with EtOAc (2×250 ml). The organic layer was washed with brine(200 ml), dried (Na₂SO₄) and concentrated to give the crude compoundwhich was purified by flash chromatography to afford the desired product(7.5 g, 71%).

Step 4:2-Chloro-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

A solution of2-chloro-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(7.5 g, 18.5 mmol, 1 eq) in THF (150 ml) was cooled to −78° C. and KOtBu(1 M solution in THF), (37.0 ml, 37.0 mmol, 2 eq) was added dropwise.The mixture was stirred for 30 min then Mel (1.7 ml, 27.75 mmol, 1.5 eq)was added and the resulting RM allowed to warm to RT and stirred for 14h. The RM was quenched with cold water (200 ml) and extracted with EtOAc(2×250 ml). The combined organic layers were washed with brine (200 ml),dried (Na₂SO₄) and concentrated. The residue upon purification by CC(silica gel; EtOAc PE) afforded [cis rac]2-chloro-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(3.5 g, 46%) [TLC system: EtOAc/PE; 4:6; Rf: 0.50].

Step 5:5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-pyrrolidin-1-yl-pyridine

To a solution of [cis rac]2-chloro-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(2 g, 4.7 mmol, 1 eq) and K₂CO₃ (1.94 g, 14.1 mmol, 3 eq) in DMF (30 ml)was added pyrrolidine (0.67 g, 9.5 mmol, 2 eq). The resulting mixturewas heated to 100° C. for 24 h. The RM was filtered through celite andthe filtrate concentrated to yield the crude product which was purifiedby flash chromatography to afford [cis rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-pyrrolidin-1-yl-pyridine(0.5 g, 24%) [TLC system: EtOAc-100%; Rf. 0.4].

Chiral resolution of [cis rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-pyrrolidin-1-yl-pyridine

[Cis rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-pyrrolidin-1-yl-pyridinewas subjected to chiral prep-SFC purification to give 102 mg of[cis-EN1] SC-400 and 105 mg of [cis-EN2] SC-401. Preparative SFCConditions: Column/dimensions: Chiralcel OJ-H (250×30)mm; CO2: 70%; Cosolvent: 30% MeOH; Total Flow: 100 g/min; Back Pressure: 100 bar; UV:253 nm.

[cis-EN1] SC-400—analytical SFC: Chiralcel OJ-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 1.94 min/specificrotation [α]_(D) ^(24.4) −10.3° (c 0.77; DCM)

[cis-EN2] SC-401—analytical SFC: Chiralcel OJ-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 2.40 min/specificrotation [α]_(D) ^(24.5) +10.2° (c 0.78; DCM)

[Trans rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-pyrrolidin-1-yl-pyridine

The corresponding [trans rac] isomer was prepared in analogy to step 5starting from [trans rac]2-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(see step 4 Example 80) to yield [trans-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-pyrrolidin-1-yl-pyridineSC-406 (40 mg) [TLC system: EtOAc-100%; Rf: 0.4].

5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(1H-[1,2,4]triazol-1-yl)-pyridine(Example 79)

Step 5:5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(1H-[1,2,4]triazol-1-yl)-pyridine

A mixture of [cis rac]2-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(see step 4, Example 80) (0.95 g, 2.04 mmol, 1 eq), Cs₂CO₃ (1.78 g, 4.08mmol, 2 eq) in DMSO (15 ml), CuI (193 mg, 1.02 mmol, 0.5 eq), and1,2,4-triazole (423 mg, 6.142 mmol, 3 eq) in a sealed tube, was heatedto 120° C. for 14 h. The RM was filtered through celite and the filtrateconcentrated to give the crude product which was purified by flashchromatography to afford [cis-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(1H-[1,2,4]triazol-1-yl)-pyridine(0.5 g, 37%) [TLC system: EtOAc-PE; 4:6; Rf: 0.2].

Chiral resolution of [cis-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(1H-[1,2,4]triazol-1-yl)-pyridine

[Cis-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(1H-[1,2,4]triazol-1-yl)-pyridinewas subjected to chiral prep-SFC purification to give 114 mg of[cis-EN1] SC-402 and 99 mg of [cis-EN2] SC-403. Preparative SFCConditions: Column/dimensions: Chiralpak AS-H (250×30) mm; CO2: 50%; Cosolvent: 50% MeOH; Total Flow: 60 g/min; Back Pressure: 100 bar; UV: 238nm.

[cis-EN1] SC-402—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 30% of 0.5% DEA in MeOH, Ret. Time 2.69 min

[cis-EN2] SC-403—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 30% of 0.5% DEA in MeOH, Ret. Time 4.73 min

[Transrac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(1H-[1,2,4]triazol-1-yl)-pyridine

The corresponding [trans rac] isomer was prepared in analogy to step 5starting from [trans rac]2-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(see step 4, Example 80) to yield [trans-rac]5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(1H-[1,2,4]triazol-1-yl)-pyridineSC-407 (40 mg) [TLC system: EtOAc-PE; 3:6; Rf: 0.2].

2-(2-Methoxy-ethoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 80)

Step 1: 2-(6-Bromopyridin-3-yl)tetrahydro-2H-pyran-4-yl methanesulfonate

To a stirred solution of 6-bromonicotinaldehyde (10 g, 53.763 mmol, 1.0eq) in DCM (100 ml), methane sulfonic acid (34.87 ml, 537.63 mmol, 10eq) was added dropwise at 0° C., followed by 3-buten-1-ol (4.6 ml,53.763, 1 eq). The RM was allowed to warm to RT and stir for 4 h.Reaction progress was monitored by TLC. The RM was neutralized to pH 7with aq. NaHCO₃ and extracted with DCM (2×300 ml). The organic layer waswashed with brine solution (100 ml)), dried (Na₂SO₄), filtered andconcentrated to afford the desired product (16 g, 88%).

Step 2:2-Bromo-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred solution of 3-trifluoromethyl thiophenol (15.9 g, 89.285mmol, 2.0 eq) in DMF (100 ml), K₂CO₃ (12.32 g, 89.285 mmol, 2.0 eq) wasadded at 0° C., followed by2-(6-bromopyridin-3-yl)tetrahydro-2H-pyran-4-yl methanesulfonate (15 g,44.642 mmol, 1 eq). The RM was then heated to 50° C. and stirred for 12h. Reaction progress was monitored by TLC. The RM was quenched with icewater (50 ml) and diluted with Et₂O (200 ml). It was then washed withwater (3×300 ml) and brine solution (300 ml), dried (Na₂SO₄), filteredand concentrated. This afforded a residue, which was purified by CC(silica gel, 25% EtOAc in PE) to give the desired product (16.7 g, 90%).

Step 3:2-Bromo-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred solution of2-bromo-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(16.7 g, 40.047 mmol, 1.0 eq) in EtOH (300 ml) and water (200 ml), Oxone(36.884 g, 120.14 mmol, 3.0 eq) was added at RT and the mixture wasstirred for 12 h. Reaction progress was monitored by TLC. The RM wasbasified with aq. NaHCO₃ and extracted with DCM (300 ml). The organiclayer was washed with water (300 ml) and brine solution (300 ml), dried(Na₂SO₄), filtered and concentrated to afford the crude product, whichwas purified by CC (silica gel, 30% EtOAc in PE) to afford the desiredproduct (15.7 g, 88%).

Step 4:2-Bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred solution of2-bromo-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(16 g, 35.634 mmol, 1.0 eq) in THF (100 ml), 1 M KOtBu in THF (71 ml,71.26 mmol, 2.0 eq) was added at −78° C. followed by Mel (3.3 ml, 53.451mmol, 1.5 eq). The RM was allowed to slowly warm to RT and then stirredfor 12 h. Reaction progress was monitored by TLC. The RM was poured intoice-water and extracted with EtOAc (500 ml). The organic layer waswashed with water (2×300 ml) and brine solution (300 ml), dried(Na₂SO₄), filtered and concentrated to afford the crude product, whichwas purified by prep HPLC to give [cis rac]2-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(6.8 g, 41%) and [trans rac]2-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(205 mg).

Step 5:2-(2-Methoxy-ethoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

To a stirred solution of [cis rac]2-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(1 g, 2.159 mmol, 1.0 eq) in DMF (20 ml), NaH (0.259 g, 6.477 mmol, 3.0eq) was added at 0° C. The mixture was then stirred at RT for 30 min,followed by addition of 2-methoxy-ethanol. Subsequently the mixture washeated to 90° C. for 12 h. Reaction progress was monitored by TLC. TheRM was cooled to RT and quenched with ice-water. It was then dilutedwith EtOAc (300 ml), washed with water (3×300 ml) and brine solution(300 ml), dried (Na₂SO₄), filtered and concentrated to afford the crudeproduct, which was purified by prep HPLC to afford [cis rac]2-(2-methoxy-ethoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(500 mg, 50%) [TLC system: EtOAc-PE; 3:7; Rf: 0.35].

Chiral resolution of [cis rac]2-(2-methoxy-ethoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

[Cis rac]2-(2-methoxy-ethoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinepyridine was subjected to chiral prep-SFC purification to give 95 mg of[cis-EN1] SC-404 and 155 mg of [cis-EN2] SC-405. Preparative SFCConditions: Column/dimensions: Chiralcel OX-H (250×30)mm; CO2: 70%; Cosolvent: 30% MeOH; Total Flow: 100 g/min; Back Pressure: 100 bar; UV:215 nm.

[cis-EN1] SC-404—analytical SFC: Chiralcel OX-H (250×4.6 mm 5μ), 26° C.,5 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 1.55 min

[cis-EN2] SC-405—analytical SFC: Chiralcel OX-H (250×4.6 mm 5μ), 26° C.,5 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 1.89 min

[Trans rac]2-(2-methoxy-ethoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

The corresponding [trans rac] isomer was prepared in analogy to step 5starting from [trans rac]2-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(see step 4) to yield [trans-rac]2-(2-methoxy-ethoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-420 (30 mg) [TLC system: EtOAc-PE; 3:7; Rf: 0.45].

Methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]amine(Example 81)

Step 5:Methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine

A mixture of [cis rac]2-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(see step 4, Example 80) (1.5 g, 4.319 mmol, 1 eq), K₂CO₃ (1.78 g, 12.9mmol, 3 eq) in DMF (20 ml), CuI (410 mg, 2.15 mmol, 0.5 eq) andmethylamine solution in MeOH (10 ml, 21.59 mmol, 10 eq) in a sealedtube, was heated to 120° C. for 24 h. The RM was filtered through celiteand the filtrate concentrated to yield the crude product which waspurified by flash chromatography to afford [cis rac]methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine(0.5 g, 37%) [TLC system: EtOAc-PE; 4:6; Rf: 0.2].

Chiral resolution of [cis-rac]methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine

[Cis-rac]methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-aminewas subjected to chiral prep-SFC purification to give 106 mg of[cis-EN1] SC-408 and 97 mg of [cis-EN2] SC-409. Preparative SFCConditions: Column/dimensions: Chiralpak AD-H (250×21) mm; CO2: 70%; Cosolvent: 30% MeOH; Total Flow: 60 g/min; Back Pressure: 100 bar; UV: 245nm.

[cis-EN1] SC-408—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 3.22 min

[cis-EN2] SC-409—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 3.95 min

[Trans rac]methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine

The corresponding [trans rac] isomer was prepared in analogy to step 5starting from [trans rac]2-bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(see step 4 Example 80) to yield [trans-rac]methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amineSC-412 (50 mg) [TLC system: EtOAc-PE; 4:6; Rf: 0.3].

2-(Difluoro-methoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 85)

Steps 1 to 4 were carried out in analogy to Example 78 (steps 1 to 4) togive, after purification by prep HPLC [cis rac]2-methoxy-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(6.1 g, step 4: 42%) and [trans rac]2-methoxy-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(600 mg). [TLC system: EtOAc-PE (3:7); R_(f): 0.45].

Step 5:5-((4-Methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridin-2-ol

A stirred solution of [cis rac]2-methoxy-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(3.5 g, 8.43 mmol, 1.0 eq) in HBr (47% aq) was heated to 150° C. for 2h. Reaction progress was monitored by TLC. The RM was cooled to RT andbasified to pH 8 with sat. NaHCO₃ solution. The mixture was extractedwith EtOAc (2×200 ml), the collected organic layer was dried overNa₂SO₄, filtered and concentrated to afford the crude product.Purification by trituration with Et₂O afforded [cis rac]5-((4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridin-2-ol(1.9 g, 56%).

Step 6:2-(Difluoro-methoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

To a stirred solution of [cis rac]5-((4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridin-2-ol(1.9 g, 4.738 mmol, 1.0 eq) in DMF (20 ml), K₂CO₃ (1.3 g, 9.47 mmol, 2.0eq) was added at RT. The mixture was heated to 90° C. and purged withFreon gas for 2 h. Reaction progress was monitored by TLC. The RM wascooled to RT, quenched with ice water and diluted with Et₂O (100 ml).The organic layer was washed with water (3×300 ml) and brine solution(300 ml), dried (Na₂SO₄), filtered and concentrated to afford the crudeproduct, which was triturated with Et₂O (10 ml) to afford [cis rac]2-(difluoro-methoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(1 g, 46%) [TLC system: EtOAc-PE (3:7); R_(F): 0.35].

Chiral resolution of [cis rac]2-(difluoro-methoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-Pyran-2-yl]-pyridine

[Cis-rac]2-(difluoro-methoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to chiral prep-SFC purification to give 135 mg of[cis-EN1] SC-418 and 195 mg [cis-EN2] SC-419. Preparative SFCConditions: Column/dimensions: Chiralcel OJ-H (250×21) mm; CO2: 85%; Cosolvent: 15% MeOH; Total Flow: 60 g/min; Back Pressure: 100 bar; UV: 212nm.

[cis-EN1] SC-418—analytical SFC: Chiralcel OJ-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 15% of 0.5% DEA in MeOH, Ret. Time 2.12 min/specificrotation [α]_(D) ^(24.7) −20.1° (c 0.85; DCM)

[cis-EN2] SC-419—analytical SFC: Chiralcel OJ-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 15% of 0.5% DEA in MeOH, Ret. Time 2.63 min/specificrotation [α]_(D) ^(24.7) +21.3° (c 0.81; DCM)

[Trans rac]2-(difluoro-methoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

The corresponding [trans rac] isomer was prepared in analogy to steps 5& 6 starting from [trans rac]2-methoxy-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridineto yield [trans-rac]2-(difluoro-methoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-417 (60 mg) [TLC system: EtOAc-PE; 3:7; Rf: 0.45].

The starting material 6-methoxynicotinaldehyde was prepared as follows:

(A) To a stirred solution of methyl 6-methoxynicotinate (14 g, 83.83mmol, 1.0 eq) in THF (300 ml), NaBH₄ (47.7 g, 1.257 mol, 15 eq) wasadded at RT, followed by MeOH (300 ml). The RM was stirred at RT for 12h. Reaction progress was monitored by TLC. The RM was quenched with sat.NH₄Cl (100 ml), diluted with water (100 ml) and extracted with EtOAc(3×200 ml). The organic layer was washed with brine solution (100 ml),dried (Na₂SO₄), filtered and concentrated to afford the crude product,which upon CC (silica gel, 40% EtOAc in PE afforded(6-methoxypyridin-3-yl)methanol (10 g, 86%).

(B) To a stirred solution of (6-methoxypyridin-3-yl)methanol (9.3 g,66.906 mmol, 1.0 eq) in DCM (300 ml), DMP (42.55 g, 100.35 mmol, 1.5 eq)was added at 0° C. The mixture was allowed to warm to RT and stir for 12h. Reaction progress was monitored by TLC. The RM was quenched with icewater (150 ml) and extracted with DCM (2×200 ml). The organic layer waswashed with brine solution (100 ml), dried (Na₂SO₄), filtered andconcentrated to afford the crude product, which was purified by CC(silica gel, 25% EtOAc in PE) to afford 6-methoxynicotinaldehyde (6 g,61%).

General Reaction Scheme for Examples 82, 83, 84, 86, 87, 89 (SC-410,SC-411, SC-413 to SC-416, SC-421 to SC-424, SC-427, SC-428 & SC-438)

2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine(Example 82)

The synthesis was carried out in analogy to Example 78 (steps 1 to 4) togive [cis rac]2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine[TLC system: EtOAc-PE; 2:3; Rf: 0.26].

Chiral resolution of [cis-rac]2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine

[Cis-rac]2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidinewas subjected to chiral prep-SFC purification to give of [cis-EN1]SC-410 and [cis-EN2] SC-411. Preparative SFC Conditions:Column/dimensions: Lux-Amylose-2 (250×30) mm; CO2: 70%; Co solvent: 30%MeOH; Total Flow: 60 g/min; Back Pressure: 100 bar; UV: 210 nm.

[cis-EN1] SC-410—analytical SFC: Lux-Amylose-2 (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 2.69 min

[cis-EN2] SC-411—analytical SFC: Lux-Amylose-2 (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 4.36 min

The starting material 2-methoxypyrimidine-5-carbaldehyde was prepared asfollows:

(A) To a solution of 2-bromoacetic acid (40 g, 289.55 mmol, 1 eq) in DMF(125 ml) was added POCl₃ (106 ml) dropwise at 0° C. and the RM wasstirred at 105° C. for 8 h. The RM was quenched with EtOH (160 ml)dropwise at 0° C., followed by THF (800 ml). The RM was stirred at 0° C.for 2 h. The precipitated crystals were filtered off, washed with (20%EtOH-THF) and dried under vacuum.

(B) To a solution of methyl carbamimidate sulfate (10 g, 81.3 mmol, 1eq) and the product from step (A) (41.30 g, 162.6 mmol, 2 eq) in^(i)PrOAc (200 ml) was added a solution of KHCO₃ (24.39 g, 243.9 mmol, 3eq) in water (100 ml) in one portion at RT. The RM was stirred at RT for48 h. It was diluted with water (100 ml) and the aq. layer was extractedwith EtOAc (3×100 ml). The organics were dried (Na₂SO₄) and concentratedto afford 2-methoxypyrimidine-5-carbaldehyde (10 g, 88%; over 2 steps).

Dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidin-2-yl]-amine(Example 83)

The synthesis was carried out in analogy to Example 78 (steps 1 to 4) togive [cis rac]dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidin-2-yl]-amine[TLC system: EtOAc-PE; 1:1; Rf. 0.24].

Chiral resolution of [cis-rac]dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidin-2-yl]-amine

[Cis-rac]dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidin-2-yl]-aminewas subjected to chiral prep-SFC purification (Chiralpak AD-H) to giveof [cis-EN1] SC-413 and [cis-EN2] SC-414.

[cis-EN1] SC-413—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 3.52 min

[cis-EN2] SC-414—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 5.15 min

The starting material 2-(dimethylamino)pyrimidine-5-carbaldehyde wasprepared as follows:

(A) To a solution of 2-bromoacetic acid (40 g, 289.55 mmol, 1 eq) in DMF(125 ml) was added POCl₃ (106 ml) dropwise at 0° C. and the RM wasstirred at 105° C. for 8 h. The RM was quenched with EtOH (160 ml)dropwise at 0° C., followed by THF (800 ml). The RM was stirred at 0° C.for 2 h. The precipitated crystals were filtered off, washed with (20%EtOH-THF) and dried under vacuum.

(B) To a solution of 1,1-dimethylguanidine hydrochloride (10 g, 81.3mmol, 1 eq) and the product from (A) (41.30 g, 162.6 mmol, 2 eq) ini-PrOAc (200 ml) was added a solution of KHCO₃ (24.39 g, 243.9 mmol, 3eq) in water (100 ml) in one portion at RT. The RM was stirred at RT for48 h. The RM was diluted with water (100 ml), and the aq. layer wasextracted with EtOAc (3×100 ml), dried (Na₂SO₄) and concentrated toafford 2-(dimethylamino)pyrimidine-5-carbaldehyde (4.8 g, 39%; over 2steps).

2-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine(Example 84)

The synthesis was carried out in analogy to Example 78 (steps 1 to 4) togive [cis rac]2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine[TLC system: EtOAc-PE; 4:6; Rf. 0.48].

Chiral resolution of [cis rac]2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine

[Cis-rac]2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazinewas subjected to chiral prep-SFC purification to give 110 mg of[cis-EN1] SC-415 and 70 mg [cis-EN2] SC-416. Preparative SFC Conditions:Column/dimensions: Chiralpak AD-H (250×30) mm; CO2: 75%; Co solvent: 25%MeOH; Total Flow: 60 g/min; Back Pressure: 100 bar; UV: 216 nm.

[cis-EN1] SC-415—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 25% of 0.5% DEA in MeOH, Ret. Time 2.79 min

[cis-EN2] SC-416—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 25% of 0.5% DEA in MeOH, Ret. Time 3.23 min

The starting material 5-methoxypyrazine-2-carbaldehyde was prepared asfollows:

(A) To a solution of methyl 5-chloropyrazine-2-carboxylate (3×5 g, 28.98mmol, 1 eq) in MeOH (50 ml), was added NaOMe (4 g, 72.45 mmol, 2.5 eq)and the RM was stirred at 60° C. for 18 h. Reaction progress wasmonitored by TLC. The RM was diluted with water (300 ml) and extractedwith EtOAc (3×200 ml). The combined organic layers were washed withbrine solution (200 ml), dried over Na₂SO₄ and concentrated to affordmethyl 5-methoxypyrazine-2-carboxylate (12 g, 82%).

(B) To a solution of methyl 5-methoxypyrazine-2-carboxylate (5 g, 29.73mmol, 1 eq) in THF (100 ml) at 0° C., was added NaBH₄ (17 g, 446.03mmol, 15 eq) portionwise, followed by dropwise addition of MeOH (100ml). The RM was stirred at RT for 3 h. Reaction progress was monitoredby TLC. The RM was quenched with sat. NH₄Cl solution at 0° C. Thesolvent was distilled off and the residue was diluted with EtOAc (3×100ml). The organic layer was washed with water (100 ml) and brine (100ml), dried over Na₂SO₄ and concentrated to afford(5-methoxypyrazin-2-yl)methanol (4.5 g, 54%).

(C) To a solution of (5-methoxypyrazin-2-yl)methanol (2 g, 10.703 mmol,1 eq) in CHCl₃ (50 ml), was added MnO₂ (9.3 g, 107.03 mmol, 10 eq) atRT. The RM was refluxed for 18 h. Reaction progress was monitored byTLC. The RM was cooled to RT, filtered through celite and washed withDCM (200 ml). The filtrate was concentrated to afford5-methoxypyrazine-2-carbaldehyde (1 g, 51%).

Dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazin-2-yl]-amine(Example 86)

The synthesis was carried out in analogy to Example 78 (steps 1 to 4) togive [cis rac]dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazin-2-yl]-amine[TLC system: EtOAc-PE; 4:6; Rf. 0.38].

Chiral resolution of [cis rac]dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazin-2-yl]-amine

[Cis-rac]dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazin-2-yl]-aminewas subjected to chiral prep-SFC purification to give 120 mg of[cis-EN1] SC-421 and 92 mg [cis-EN2] SC-422. Preparative SFC Conditions:Column/dimensions: Chiralpak AD-H (250×30) mm; CO2: 60%; Co solvent: 40%of 0.5% DEA in MeOH; Total Flow: 100 g/min; Back Pressure: 100 bar; UV:254 nm.

[cis-EN1] SC-421—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 2.91 min

[cis-EN2] SC-422—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 26° C.,3 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 3.75 min

The starting material 5-(dimethylamino)pyrazine-2-carbaldehyde wasprepared as follows:

(A) To a solution of methyl 5-chloropyrazine-2-carboxylate (5 g, 28.98mmol, 1 eq) in DMF (30 ml), was added K₂CO₃ (12 g, 86.94 mmol, 3 eq)followed by Me₂NH.HCl. The RM mixture was stirred at 60° C. for 18 h.Reaction progress was monitored by TLC. The RM was diluted with water(200 ml) and extracted with EtOAc (2×200 ml). The combined organiclayers were washed with water (2×150 ml) and brine solution (100 ml),dried over Na₂SO₄ and concentrated to afford methyl5-(dimethylamino)pyrazine-2-carboxylate (3 g, 57%).

(B) (5-(Dimethylamino)pyrazin-2-yl)methanol was prepared in analogy tostep (B) Example 84.

(C) 5-(Dimethylamino)pyrazine-2-carbaldehyde was prepared in analogy tostep (C) Example 84.

5-Methoxy-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine(Example 87)

The synthesis was carried out in analogy to Example 78 (steps 1 to 4) togive [cis rac]5-methoxy-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine[TLC system: EtOAc-PE; 1:1; Rf. 0.26].

Chiral resolution of [cis rac]5-methoxy-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine

[Cis-rac]5-methoxy-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidinewas subjected to chiral prep-SFC purification to give 100 mg of[cis-EN1] SC-423 and 60 mg [cis-EN2] SC-424. Preparative SFC Conditions:Column/dimensions: LuxCellulose-2 (250×30) mm; CO2: 60%; Co solvent: 40%MeOH; Total Flow: 100 g/min; Back Pressure: 100 bar; UV: 217 nm.

[cis-EN1] SC-423—analytical SFC: LuxCellulose-2 (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 30% of 0.5% DEA in MeOH, Ret. Time 2.97 min

[cis-EN2] SC-424—analytical SFC: LuxCellulose-2 (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 30% of 0.5% DEA in MeOH, Ret. Time 5.28 min

The starting material 5-methoxypyrimidine-2-carbaldehyde was prepared asfollows:

(A) A mixture of 2-chloro-5-methoxypyrimidine (10 g, 69.44 mmol, 1 eq)MeOH—CH₃CN 4:1 (160 ml-40 ml), TEA (20 ml) and Pd(dppf)Cl₂ DCM (6 g,7.34 mmol, 0.1 eq) in an autoclave, was stirred at 100° C. for 18 hunder CO gas atmosphere. The RM was cooled to RT, filtered throughcelite, washed with MeOH (100 ml), and the filtrate was concentrated.The residue upon purification by CC (silica gel; EtOAc PE; 3:7) affordedmethyl 5-methoxypyrimidine-2-carboxylate (6 g, 52%).

(B) (5-Methoxypyrimidin-2-yl)methanol was prepared in analogy to step(B) Example 84.

(C) 5-Methoxypyrimidine-2-carbaldehyde was prepared in analogy to step(C) Example 84. This filtered CHCl₃ solution of the product was usednext step without further purification.

3-Chloro-5-(difluoro-methoxy)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 89)

The synthesis was carried out in analogy to example 78 (steps 1 to 4) togive, upon purification by flash chromatography (silica-gel; 15-20%EtOAc in PE) [cis rac]3-chloro-5-(difluoro-methoxy)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(0.6 g, step 4: 20%) [TLC system: EtOAc-PE; 3:7; Rf: 0.4] and [transrac]3-chloro-5-(difluoro-methoxy)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridineSC-438 (26 mg) [TLC system: EtOAc-PE; 3:7; Rf: 0.5].

Chiral resolution of [cis-rac]3-chloro-5-(difluoro-methoxy)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

[Cis-rac]3-chloro-5-(difluoro-methoxy)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to chiral prep-SFC purification to give of [cis-EN1]SC-427 and [cis-EN2] SC-428. Preparative SFC Conditions:Column/dimensions: Chiralpak AS-H (250×30) mm; CO2: 85%; Co solvent: 15%MeOH; Total Flow: 100 g/min; Back Pressure: 100 bar; UV: 212 nm.

[cis-EN1] SC-410—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 15% of 0.5% DEA in MeOH, Ret. Time 1.92 min [cis-EN2]SC-411—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 30° C., 3 g/min,100 bar, 15% of 0.5% DEA in MeOH, Ret. Time 2.35 min

The starting material 3-chloro-5-(difluoromethoxy)picolinaldehyde wasprepared as follows:

(A) To a solution of 5,6-dichloropyridin-3-ol (8.5 g, 52.14 mmol, 1 eq)in EtOH (60 ml) was added Pd(dppf)Cl₂ (4.25 g, 5.21 mmol, 0.1 eq),Pd(OAc)₂ (1.16 g, 5.21 mmol, 0.1 eq) and CH₃COONa (4.27 g, 52.14 mmol, 1eq). The RM was stirred in a steel bomb filled with CO gas (250 psi) at90° C. for 14 h. After completion (monitored by TLC), the RM wasfiltered through celite. The filtrate was concentrated to give the crudeproduct, which was purified by CC (silica-gel, 30-40% EtOAc in PE) toafford ethyl 3-chloro-5-hydroxypicolinate (8.5 g, 81%).

(B) To a solution of ethyl 3-chloro-5-hydroxypicolinate (7.5 g, 37.3mmol, 1 eq) in DMF (70 ml), was added K₂CO₃ (10.2 g, 74.6 mmol, 2 eq).The mixture was stirred at 90° C., then Freon gas was bubbled throughfor 1 h. After completion (monitored by TLC), the RM was diluted withice-cold water and extracted with EtOAc (3×100 ml). The organics werewashed with water (100 ml) and brine (100 ml), dried (Na₂SO₄) andconcentrated to give the crude product, which was purified by CC(silica-gel, 20-25% EtOAc in PE) to afford ethyl3-chloro-5-(difluoromethoxy)picolinate (5.6 g, 62%).

(C) To a solution of ethyl 3-chloro-5-(difluoromethoxy)picolinate (5.6g, 22.3 mmol, 1 eq) in MeOH (50 ml), was added NaBH₄ (4.2 g, 11.5 mmol,5 eq) at 0° C. and the RM was stirred at RT for 4 h. After completion(monitored by TLC), the RM was quenched with ice-water (200 ml), MeOHwas distilled off and the mixture was extracted with EtOAc (3×200 ml).The combined organic layers were washed with brine (300 ml), dried(Na₂SO₄) and concentrated to afford(3-chloro-5-(difluoromethoxy)pyridin-2-yl)methanol (4.3 g).

(D) To a solution of (3-chloro-5-(difluoromethoxy)pyridin-2-yl)methanol(4.3 g, 20.57 mmol, 1 eq) in DCM (50 ml) was added, DMP (13 g, 30.08mmol, 1.5 eq) at 0° C. and the mixture was stirred for 16 h at RT. Aftercompletion (monitored by TLC), the mixture was filtered through a bed ofcelite. The filtrate was diluted with water (200 ml) and extracted EtOAc(3×200 ml). The organics were washed with water (200 ml), sat NaHCO₃(200 ml) and brine (200 ml), dried (Na₂SO₄) and the solvent wasdistilled off under reduced pressure. The crude product was purified byCC (silica-gel, 15-20% EtOAc in PE) to afford3-chloro-5-(difluoromethoxy)picolinaldehyde (3.1 g, 67%, over 2 steps).

General Reaction Scheme for Examples 88, 93 99 (SC-425, SC-426, SC-435,SC-439 to SC-450, SC-452 to SC-454)

3-Chloro-5-cyclopropyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 88)

Steps 1 to 4 were carried out in analogy to Example 78 (steps 1 to 4) togive, after trituration with 50% ether in PE, [cis rac]5-bromo-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(3 g, step 4: 73%). The filtrate was purified further by prep-HPLC togive [trans rac]5-bromo-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(0.25 g). [TLC system: EtOAc-PE (2:8); R_(f): 0.37]

Step 5:3-Chloro-5-cyclopropyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred solution of [cis rac]5-bromo-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(2 g, 4.02 mmol, 1.0 eq) and cyclopropylboronic acid (0.52 g, 6.03 mmol,1.5 eq) in toluene (50 ml) and water (1 ml), Cs₂CO₃ (2.61 g, 8.04 mmol,2 eq) was added. The mixture was purged with Ar for 10 min, thenPd(dppf)Cl₂ was added and it was again purged with Ar for 10 min. The RMwas heated to 90° C. for 12 h. The mixture was cooled to RT and passedthrough celite. The filtrate was concentrated to give the crude product,which was purified by CC (silica gel) to afford [cis rac]3-chloro-5-cyclopropyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(0.6 g, 33%) [TLC system: EtOAc-PE, 3:7; R_(F): 0.12].

Chiral resolution of [cis rac]3-chloro-5-cyclopropyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

[Cis-rac]3-chloro-5-cyclopropyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridinewas subjected to chiral prep-SFC purification to give 160 mg of[cis-EN1] SC-425 and 175 mg [cis-EN2] SC-426. Preparative SFCConditions: Column/dimensions: Lux-Cellulose-2 (250×30) mm; CO2: 60%; Cosolvent: 40% MeOH; Total Flow: 90 g/min; Back Pressure: 100 bar; UV: 220nm.

[cis-EN1] SC-425—analytical SFC: Lux-Cellulose-2 (250×4.6 mm 5μ), 30°C., 3 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 2.62 min

[cis-EN2] SC-426—analytical SFC: Lux-Cellulose-2 (250×4.6 mm 5μ), 30°C., 3 g/min, 100 bar, 40% of 0.5% DEA in MeOH, Ret. Time 3.77 min

[Trans rac]3-chloro-5-cyclopropyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

The corresponding [trans rac] isomer was prepared in analogy to step 5starting from [trans rac]5-bromo-3-chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridineto yield [trans-rac]3-chloro-5-cyclopropyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridineSC-435 (45 mg) [TLC system: EtOAc-PE; 3:7; Rf: 0.45].

The starting material 5-bromo-3-chloropicolinaldehyde was prepared asfollows:

5-Bromo-3-chloropicolinaldehyde was prepared in 2 steps from methyl5-bromo-3-chloropicolinate. The synthesis was carried out in analogy tothe methods described for the preparation of 6-methoxynicotinaldehyde,the starting material for Example 85.

3-Chloro-2-[4-[(3-chlorophenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine(Example 93)

Steps 1 to 4 were carried out in analogy to Example 78(steps 1 to 4) togive, after purification by Prep-HPLC, [cis rac]5-bromo-3-chloro-2-(4-((3-chlorophenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)pyridine(750 mg, step 4: 14%). [TLC system: EtOAc-PE (4:6); R_(f): 0.68].

Step 5:3-Chloro-2-(4-((3-chlorophenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)-5-(methylthio)pyridine

To a solution of [cis rac]5-bromo-3-chloro-2-(4-((3-chlorophenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)pyridine(750 mg, 1.619 mmol, 1 eq) and DIPEA (0.8 ml, 4.859 mmol, 3 eq) intoluene (50 ml) was added NaSMe (170 mg, 2.429 mmol, 1.5 eq). Themixture was degassed for 10 min and Xantphos (66 mg, 0.113 mmol, 0.07eq), followed by Pd₂(dba)₃ (104 mg, 0.113 mmol, 0.07 eq) was added. Themixture was again degassed for 10 min. The RM was heated to 110° C. for18 h under Ar. The reaction was monitored by TLC, and after completionfiltered through celite. The filtrate was concentrated to yield thecrude product which was purified by flash chromatography to afford [cisrac]3-chloro-2-(4-((3-chlorophenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)-5-(methylthio)pyridine(400 mg, 57%).

Step 6:3-Chloro-2-[4-[(3-chlorophenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine

Oxone (1.7 g, 2.784 mmol, 3 eq) in water (15 ml) was added to a solutionof [cis rac]3-chloro-2-(4-((3-chlorophenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)-5-(methylthio)pyridine(400 mg, 0.928 mmol, 1 eq) in EtOH (25 ml) at RT and stirred for 18 h.The reaction was monitored by TLC. EtOH was distilled off under reducedpressure and the residue was diluted with H₂O (50 ml) and extracted withEtOAc (2×50 ml). The organics were washed with aq NaHCO₃ (100 ml), water(100 ml) and brine (50 ml), dried (Na₂SO₄) and concentrated to give thecrude product which was purified by flash chromatography to afford [cisrac]3-chloro-2-[4-[(3-chlorophenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine(300 mg, 70%) [TLC system: EtOAc-PE; 7:3; RF: 0.48].

Chiral resolution of [cis rac]3-chloro-2-[4-[(3-chlorophenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine

[Cis-rac]3-chloro-2-[4-[(3-chlorophenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridinewas subjected to chiral prep-SFC purification to give 130 mg of[cis-EN1] SC-439 and 160 mg [cis-EN2] SC-440. Preparative SFCConditions: Column/dimensions: Chiralcel OJ-H (250×30) mm; CO2: 70%; Cosolvent: 30% MeOH; Total Flow: 90 g/min; Back Pressure: 100 bar; UV: 217nm.

[cis-EN1] SC-439—analytical SFC: Chiralcel OJ-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 30% MeOH, Ret. Time 3.4 min

[cis-EN2] SC-440—analytical SFC: Chiralcel OJ-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 30% MeOH, Ret. Time 4.2 min

The starting material 5-bromo-3-chloropicolinaldehyde was prepared asfollows:

5-Bromo-3-chloropicolinaldehyde was prepared in 2 steps from methyl5-bromo-3-chloropicolinate. The synthesis was carried out in analogy tothe methods described for the preparation of 6-methoxynicotinaldehyde,the starting material for Example 85.

3-Methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 94)

The synthesis was carried out in analogy to Example 95 to afford [transrac]3-methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(105 mg) [TLC system: EtOAc-PE; 3:2; RF: 0.34].

2-[4-[[3-(Difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridine(Example 95)

Steps 1 to 4 were carried out in analogy to Example 78 (steps 1 to 4).The crude product after work-up was washed with 50% Et₂O PE, filteredand dried under vacuum to afford [cis rac]5-bromo-2-(4-((3-(difluoromethyl)-5-fluorophenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)-3-methylpyridine(1.3 g; step 4: 70%) [TLC system: EtOAc-PE; 3:7; Rf: 0.53]. The filtrateupon concentration and purification by flash chromatography afforded[trans rac]5-bromo-2-(4-((3-(difluoromethyl)-5-fluorophenyl)-sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)-3-methylpyridine(140 mg) [TLC system: EtOAc-PE; 3:7; Rf: 0.54].

Steps 5 & 6 were carried out in analogy to Example 93 to afford [cisrac]2-[4-[[3-(difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridine(700 mg, 70%) [TLC system: EtOAc-PE; 6:4; RF: 0.38].

Chiral resolution of [cis rac]2-[4-[[3-(difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridine

[Cis-rac]2-[4-[[3-(difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridinewas subjected to chiral prep-SFC purification to give 235 mg of[cis-EN1] SC-442 and 230 mg [cis-EN2] SC-443. Preparative SFCConditions: Column/dimensions: Chiralpak AS-H (250×30) mm; CO2: 70%; Cosolvent: 30% MeOH; Total Flow: 90 g/min; Back Pressure: 100 bar; UV: 213nm.

[cis-EN1] SC-442—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 20% MeOH, Ret. Time 3.18 min

[cis-EN2] SC-443—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 20% MeOH, Ret. Time 4.32 min

[Trans rac]2-[4-[[3-(difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridine

The corresponding [trans rac] isomer was prepared in analogy to step 5 &6 starting from [trans rac]5-bromo-2-(4-((3-(difluoromethyl)-5-fluorophenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)-3-methylpyridine to yield [trans-rac]2-[4-[[3-(difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridineSC-448 (20 mg) [TLC system: EtOAc-PE; 6:4; Rf: 0.41].

The starting material 5-bromo-3-methylpicolinaldehyde was prepared asfollows:

To a solution of 2,5-dibromo-3-methylpyridine (30 g, 119.52 mmol, 1 eq)in DCM (300 ml) was added n-BuLi (2.5 M in THF, 47.8 ml, 119.52 mmol, 1eq) dropwise at −78° C. After 30 min DMF (11.1 ml, 143.42 mmol, 1.2 eq)was added at the same temperature. The RM was stirred at RT for 1.5 h.The mixture was quenched with sat. NH₄Cl solution (300 ml) and extractedwith DCM (3×300 ml). The combined organic layers were washed with brine(300 ml), dried (Na₂SO₄) and concentrated. Purification by flashchromatography afforded 5-bromo-3-methylpicolinaldehyde (9.5 g, 40%).

The starting material 3-(difluoromethyl)-5-fluorobenzenethiol wasprepared as follows:

(A) To a solution of 3-bromo-5-fluorobenzaldehyde (15 g, 73.89 mmol, 1eq) in DCM (150 ml) was added DAST (39 ml, 295.5 mmol 4 eq) dropwise at−78° C. and the mixture was stirred at RT for 16 h. After completion ofthe reaction, the mixture was poured into ice-cold water and basifiedwith sat. NaHCO₃ solution. The mixture was then extracted with DCM(3×200 ml), washed with water (200 ml) and brine (200 ml), dried(Na₂SO₄), and concentrated in vacuum to give the crude product, whichwas purified by flash chromatography to afford1-bromo-3-(difluoromethyl)-5-fluorobenzene (10 g, 60%).

(B) To a solution of 1-bromo-3-(difluoromethyl)-5-fluorobenzene (8.6 g,38.56 mmol, 1 eq) and DIPEA (13.44 ml, 77.12 mmol, 2 eq) in 1,4-dioxane(150 ml) was added PMB-SH (5.89 ml, 42.42 mmol, 1.1 eq). The mixture wasdegassed for 10 min, and Xantphos (1.56 g, 2.69 mmol, 0.07 eq), followedby Pd₂(dba)₃ (1.0 g, 1.15 mmol, 0.03 eq) were added. The mixture wasagain degassed for 10 min. The resulting RM was heated to 90° C. andstirred for 2 h under Ar. The RM was filtered through celite and thefiltrate concentrated to yield the crude product, which upon flashchromatography afforded 1-bromo-3-(difluoromethyl)-5-fluorobenzene (10g, 87%).

(C) To a solution of 1-bromo-3-(difluoromethyl)-5-fluorobenzene (10 g,33.55 mmol, 1 eq) in anisole (10 ml) was added TFA (20 ml) at RT. The RMwas stirred at 80° C. for 2 h. After completion of the reaction, themixture was diluted with water (200 ml) and extracted with EtOAc (3×200ml). The organics were washed with water (200 ml) and brine (200 ml),dried (Na₂SO₄), and concentrated in vacuum to afford3-(difluoromethyl)-5-fluorobenzenethiol (3.3 g, 55%).

2-[4-[[3-Fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridine(Example 96)

Steps 1 to 4 were carried out in analogy to Example 78(steps 1 to 4).The crude product after work-up was purified by flash CC (0-15% EtOAc inPE) to afford [cis rac]5-bromo-2-(4-((3-fluoro-5-(trifluoromethyl)phenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)-3-methylpyridine(800 mg; step 4: 82%) and [trans rac]5-bromo-2-(4-((3-fluoro-5-(trifluoromethyl)phenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)-3-methylpyridine(400 mg). [TLC system: EtOAc PE; 2:3; Rf: 0.28].

Steps 5 & 6 were carried out in analogy to Example 93 to afford [cisrac]2-[4-[[3-fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridine(280 mg, 75%) [TLC system: EtOAc-PE; 3:7; RF: 0.26].

Chiral resolution of [cis rac]2-[4-[[3-fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridine

[Cis-rac]2-[4-[[3-fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridinewas subjected to chiral prep-SFC purification to give 100 mg of[cis-EN1] SC-444 and 112 mg [cis-EN2] SC-445. Preparative SFCConditions: Column/dimensions: Chiralpak AS-H (250×30) mm; CO2: 80%; Cosolvent: 20% MeOH; Total Flow: 60 g/min; Back Pressure: 100 bar; UV: 213nm.

[cis-EN1] SC-444—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 10% MeOH, Ret. Time 3.31 min

[cis-EN2] SC-445—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 10% MeOH, Ret. Time 4.72 min

[Trans rac]2-[4-[[3-fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridine

The corresponding [trans rac] isomer was prepared in analogy to step 5 &6 starting from [trans rac]5-bromo-2-(4-((3-fluoro-5-(trifluoromethyl)phenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)-3-methylpyridineto yield [trans-rac]2-[4-[[3-fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridineSC-454 (28 mg) [TLC system: EtOAc-PE; 3:7; Rf: 0.27].

The starting material 5-bromo-3-methylpicolinaldehyde was prepared asfollows:

The synthesis is described above (see Example 95).

3-Chloro-2-[4-[(3-isopropyl-phenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine(Example 97)

The synthesis was carried out in analogy to Example 93 to afford [cisrac]3-chloro-2-[4-[(3-isopropyl-phenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine(600 mg, step 6: 56%) [TLC system: EtOAc-PE; 2:3; RF: 0.40].

Chiral resolution of [cis rac]3-chloro-2-[4-[(3-isopropyl-phenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine

[Cis-rac]3-chloro-2-[4-[(3-isopropyl-phenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridinewas subjected to chiral prep-SFC purification to give 190 mg of

[cis-EN1] SC-446 and 195 mg [cis-EN2] SC-447. Preparative SFCConditions: Column/dimensions: Chiralpak AD-H (250×30) mm; CO2: 50%; Cosolvent: 50% MeOH; Total Flow: 70 g/min; Back Pressure: 100 bar; UV: 216nm.

[cis-EN1] SC-446—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 30° C.,4 g/min, 100 bar, 40% MeOH, Ret. Time 3.57 min

[cis-EN2] SC-447—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 30° C.,4 g/min, 100 bar, 40% MeOH, Ret. Time 4.48 min

3-Methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(Example 98)

The synthesis was carried out in analogy to Example 95 to afford [cisrac]3-methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(690 mg, step 6: 65%) [TLC system: EtOAc-PE; 2:3; RF: 0.20].

Chiral resolution of [cis rac]3-methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-Pyran-2-yl]-pyridine

[Cis-rac]3-methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridinewas subjected to chiral prep-SFC purification to give 190 mg of[cis-EN1] SC-449 and 220 mg [cis-EN2] SC-450. Preparative SFCConditions: Column/dimensions: Chiralpak AS-H (250×21) mm; CO2: 50%; Cosolvent: 50% MeOH; Total Flow: 60 g/min; Back Pressure: 100 bar; UV: 214nm.

[cis-EN1] SC-449—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 30% MeOH, Ret. Time 2.06 min

[cis-EN2] SC-450—analytical SFC: Chiralpak AS-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 30% MeOH, Ret. Time 2.65 min

[Trans rac]3-methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine

The synthesis was carried out in analogy to Example 95 to afford [transrac]3-methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine(80 mg) [TLC system: EtOAc-PE; 2:3; RF: 0.21].

3-[[2-(3-Chloro-5-methylsulfonyl-pyridin-2-yl)-4-methyl-tetrahydro-pyran-4-yl]sulfonyl]-benzonitrile(Example 99)

The synthesis was carried out in analogy to Example 93 to afford [cisrac]3-[[2-(3-chloro-5-methylsulfonyl-pyridin-2-yl)-4-methyl-tetrahydro-pyran-4-yl]sulfonyl]-benzonitrile(770 mg, step 6: 80%) [TLC system: EtOAc-PE; 7:3; RF: 0.38].

Chiral resolution of [cis rac]3-[[2-(3-chloro-5-methylsulfonyl-pyridin-2-yl)-4-methyl-tetrahydro-pyran-4-yl]sulfonyl]-benzonitrile

[Cis-rac]3-[[2-(3-chloro-5-methylsulfonyl-pyridin-2-yl)-4-methyl-tetrahydro-pyran-4-yl]sulfonyl]-benzonitrilewas subjected to chiral prep-SFC purification to give 149 mg of[cis-EN1] SC-452 and 135 mg [cis-EN2] SC-453. Preparative SFCConditions: Column/dimensions: Chiralcel OJ-H (250×30) mm; CO2: 60%; Cosolvent: 40% MeOH; Total Flow: 60 g/min; Back Pressure: 100 bar; UV: 218nm.

[cis-EN1] SC-452—analytical SFC: Chiralcel OJ-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 30% MeOH, Ret. Time 3.84 min

[cis-EN2] SC-453—analytical SFC: Chiralcel OJ-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 30% MeOH, Ret. Time 4.77 min

The starting material 3-mercaptobenzonitrile was prepared as follows:

To a stirred solution of 3-iodobenzonitrile (20 g, 87.33 mmol, 1.0 eq)in DMF (300 ml), was added sequentially K₂CO₃ (24 g, 174.66 mmol, 2.0eq), CuI (1.65 g, 8.73 mmol, 0.1 eq) and sulfur powder (8.38 g, 261.9mmol, 3.0 eq). The resulting RM was heated to 90° C. and stirred for 14h. The RM was cooled to 0° C. and flushed with Ar. Triphenyl phosphine(13.1 g, 50.37 mmol, 1.5 eq) was added, followed by conc. HCl (1.5 ml).The RM was heated to 110° C. and stirred at this temperature for 14 h.3-mercaptobenzonitrile was used as such in the next step reactionwithout any further purification.

Reaction scheme for Example 92 (SC-436 & SC-437)

3-Chloro-2-[4-[[3-(difluoro-methoxy)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine(Example 92)

Step 1: 2-(5-Bromo-3-chloropyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

Methane sulfonic acid (35.7 ml, 550.45 mmol, 10 eq) was added to asolution of 5-bromo-3-chloropicolinaldehyde (see Example 88) (12 g,55.04 mmol, 1 eq) in DCM (200 ml) at 0° C. But-3-en-1-ol (4.5 ml, 55.04mmol, 1 eq) was added and the mixture stirred for 16 h at RT. The RM wasquenched with sat. Na₂CO₃ solution and extracted with DCM (3×150 ml).The organics were washed with water (150 ml) and brine (150 ml), dried(Na₂SO₄) and the solvent was distilled-off under reduced pressure toafford the desired product (18 g).

Step 2:3-((2-(5-Bromo-3-chloropyridin-2-yl)tetrahydro-2H-pyran-4-yl)thio)phenol

To a solution of 3-Hydroxythiophenol (4.46 ml, 43.47 mmol, 2 eq) in DMF(200 ml) was added K₂CO₃ (5.99 g, 43.47 mmol 2 eq) and2-(5-bromo-3-chloropyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (8 g, 21.73 mmol, 1 eq). The RM was heated to 50° C.for 6 h and was then stirred at RT for 10 h. The RM was diluted withcold water (300 ml) and extracted with EtOAc (200 ml). The organics werewashed with water (200 ml) and brine (200 ml), dried (Na₂SO₄) andconcentrated under reduced pressure. The crude product was purified byflash chromatography (silica gel; EtOAc-PE; 0:100 to 15:85) to affordthe desired product (5 g, 45%).

Step 3:5-Bromo-3-chloro-2-(4-((3-(difluoromethoxy)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

To a solution of3-((2-(5-bromo-3-chloropyridin-2-yl)tetrahydro-2H-pyran-4-yl)thio)phenol(5.0 g, 12.53 mmol, 1 eq) in DMF (150 ml), was added K₂CO₃ (3.45 g,25.06 mmol, 2 eq) and the RM was heated to 90° C. The mixture was purgedwith Freon gas for 2 h at the same temperature. The RM was diluted withcold water and extracted with EtOAc (3×100 ml). The combined organiclayers were washed with water (100 ml) and brine (100 ml), dried(Na₂SO₄) and concentrated to give the crude product, which uponpurification by flash chromatography (silica gel; EtOAc: PE; 0:100 to4:96) afforded the desired product (1.3 g, 12% over 3 steps).

Step 4:5-Bromo-3-chloro-2-(4-((3-(difluoromethoxy)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

Oxone (2.6 g, 8.68 mmol, 3 eq) in water (25 ml) was added to a solutionof5-bromo-3-chloro-2-(4-((3-(difluoromethoxy)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(1.3 g, 2.89 mmol, 1 eq) in MeOH (50 ml) at RT and the mixture wasstirred for 18 h. MeOH was removed under reduced pressure, and theresidue was diluted with H₂O (50 ml) and extracted with EtOAc (3×50 ml).The organics were washed with water (50 ml) and brine (50 ml), dried(Na₂SO₄) and concentrated to give the crude product which uponpurification by flash chromatography (silica gel; EtOAc: PE; 0:100 to17:83) afforded the desired product (1.0 g, 71%).

Step 5:5-Bromo-3-chloro-2-((2R,4S)-4-((3-(difluoromethoxy)phenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)pyridine

A solution of5-bromo-3-chloro-2-(4-((3-(difluoromethoxy)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(1.0 g, 2.07 mmol, 1 eq) in THF (40 ml) was cooled to −78° C. and t-BuOK(1M in THF; 4.15 ml, 4.15 mmol, 2 eq) was added dropwise. The mixturewas stirred for 30 min, then Mel (0.19 ml, 3.11 mmol, 1.5 eq) was addedand the resulting mixture was allowed to warm to RT and stir for 16 h.The RM was quenched with water (50 ml) and extracted with EtOAc (3×50ml). The combined organic layers were washed with water (50 ml) andbrine (50 ml), dried (Na₂SO₄) and concentrated. The residue uponpurification by flash chromatography (silica gel, EtOAc: PE, 0:100 to14:86) afforded [cis rac]5-bromo-3-chloro-2-((2R,4S)-4-((3-(difluoromethoxy)phenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)pyridine(840 mg, 84%) [TLC system: EtOAc PE; 3:7; Rf: 0.51].

Step 5:3-Chloro-2-(4-((3-(difluoromethoxy)phenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)-5-(methylthio)pyridine

A solution of [cis rac]5-bromo-3-chloro-2-((2R,4S)-4-((3-(difluoromethoxy)phenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)pyridine(950 mg, 1.91 mmol, 1 eq) and DIPEA (1 ml, 5.75 mmol, 3 eq) in toluene(30 ml) was treated with NaSMe (201 mg, 2.87 mmol, 1.5 eq). The mixturewas degassed with Ar for 10 min, and Xantphos (110 mg, 0.191 mmol, 0.1eq), followed by Pd₂(dba)₃ (123 mg, 0.131 mmol, 0.07 eq) were added. TheRM was again degassed for 10 min. The resulting mixture was heated to100° C. and stirred for 18 h. The RM was filtered through celite and thefiltrate concentrated to yield the crude product which upon purificationby flash chromatography (silica gel; EtOAc: PE; 0:100 to 18:82) afforded[cis rac]3-chloro-2-(4-((3-(difluoromethoxy)phenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)-5-(methylthio)pyridine(600 mg, 67%).

Step 6:3-Chloro-2-[4-[[3-(difluoro-methoxy)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine

A solution of Oxone (1.19 g, 3.88 mmol, 3 eq) in water (10 ml) was addedto a solution of [cis rac]3-chloro-2-(4-((3-(difluoromethoxy)phenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-2-yl)-5-(methylthio)pyridine(600 mg, 1.29 mmol, 1 eq) in MeOH (20 ml) at RT and the mixture wasstirred for 18 h. MeOH was distilled-off under reduced pressure and theresidue was diluted with H₂O (50 ml) and extracted with EtOAc (3×50 ml).The organics were washed with water (50 ml) and brine (50 ml), dried(Na₂SO₄) and concentrated to give the crude product, which was purifiedflash chromatography (silica gel; EtOAc: PE; 0:100 to 28:72) to afford[cis rac]3-chloro-2-[4-[[3-(difluoro-methoxy)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine(500 mg, 78%) [TLC system: EtOAc-PE; 1:1; Rf: 0.38].

Chiral resolution of [cis rac]3-chloro-2-[4-[[3-(difluoro-methoxy)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine

[Cis-rac]3-chloro-2-[4-[[3-(difluoro-methoxy)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridinewas subjected to chiral prep-SFC purification to give 180 mg of[cis-EN1] SC-436 and 160 mg [cis-EN2] SC-437. Preparative SFCConditions: Column/dimensions: Chiralcel OJ-H (250×21) mm; CO2: 70%; Cosolvent: 30% MeOH; Total Flow: 90 g/min; Back Pressure: 100 bar; UV: 215nm.

[cis-EN1] SC-436—1^(st) eluting enantiomer

[cis-EN2] SC-437—2^(nd) eluting enantiomer

General Reaction Scheme for Examples 90-91 (SC-429 to SC-434)+NEWCOMPOUNDS

1-Methyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole(Example 90)

Step 1: 3,5-Bibromo-1H-pyrazole

To a solution of 3,4,5-tribromo-1H-pyrazole (25 g, 82 mmol, 1.0 eq) inTHF (300 ml), was added n-BuLi (2.5 M in hexanes, 82.0 ml, 205 mmol, 2.5eq) over 30 min at −78° C. and the RM was stirred at this temperaturefor 1 h. The RM was quenched by dropwise addition of MeOH-THF (2:3; 150ml) at −78° C., and the mixture was stirred for an additional 2 hallowing to warm RT gradually. The solvent was removed under reducedpressure. The residue was diluted with Et₂O (600 ml), washed with dil.HCl (0.5N, 60 ml) and brine (75 ml), dried (Na₂SO₄), filtered andconcentrated under reduced pressure to afford the desired product (12.5g, 67%).

Step 2: 3,5-Bibromo-1-methyl-1H-pyrazole

A solution of 3,5-dibromo-1H-pyrazole (25 g, 111.60 mmol, 1.0 eq) in THF(150 ml) was added to a suspension of NaH (60%; 13.30 g, 334.8 mmol, 3.0eq) in THF (150 ml) at 0° C. The mixture was stirred for 1 h beforeadding Mel (18.0 ml, 279.0 mmol, 2.5 eq). The RM was stirred at 0° C.for 3 h and then allowed to RT, and stirred for a further 12 h. The RMwas quenched with cold water (500 ml) and extracted with EtOAc (3×200ml). The combined organic layers were washed with water (2×200 ml) andbrine solution (200 ml), dried (Na₂SO₄), filtered and concentrated underreduced pressure to afford the desired product (15 g, 57%).

Step 3: 3-Bromo-1-methyl-1H-pyrazole-5-carbaldehyde

A stirred solution of 3,5-dibromo-1-methyl-1H-pyrazole (15 g, 62.5 mmol,1.0 eq) in THF (300 ml) was treated with iPrMgCl (2.0M, 56.5 ml, 112.5mmol, 1.8 eq) at −78° C. The mixture was stirred for 30 min, and DMF(14.7 ml, 187.5 mmol, 3.0 eq) was added. The RM was allowed to graduallywarm to RT, and stirred for 5 h. The RM was quenched with aq. NH₄Cl (300ml) and extracted with EtOAc (3×150 ml). The combined organic layerswere washed with water (2×150 ml) and brine (150 ml), dried (Na₂SO₄),filtered and concentrated under reduced pressure to afford the desiredproduct (11.0 g).

Step 4: 2-(3-Bromo-1-methyl-1H-pyrazol-5-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate

A stirred solution of 3-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (11.0g, 58.5 mmol, 1.0 eq) in DCM (250 ml) was treated with MsOH (36.4 ml,585.1 mmol, 10.0 eq) at 0° C. The mixture was stirred for 10 min andbut-3-en-1-ol (4.8 ml, 58.5 mmol, 1.0 eq) was added. The RM was allowedto warm to RT and stir for 18 h. The RM was quenched with sat. aq.Na₂CO₃ (150 ml) and extracted with DCM (2×200 ml). The combined organiclayers were washed with water (2×150 ml) and brine (150 ml), dried(Na₂SO₄), filtered and concentrated under reduced pressure. The residueupon purification by flash chromatography (silica-gel; EtOAc-PE; 20:80to 50:50) afforded the desired product (13.5 g, 78% over 2 steps).

Step 5:3-Bromo-1-methyl-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A stirred solution of 3-(trifluoromethyl)benzenethiol (27.3 g, 199.70mmol, 2.5 eq) in DMF (250 ml) was treated with K₂CO₃ (33.0 g, 239.65mmol, 3.0 eq). The mixture was stirred for 10 min at RT and a solutionof 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (37.0 g, 80.0 mmol, 1.0 eq) in DMF (150 ml) was added.The resulting RM was heated to 50° C., stirred for 6 h, then brought toRT and stirred for additional 10 h. The RM was concentrated underreduced pressure, and the residue was diluted with water (500 ml) andextracted with EtOAc (3×200 ml). The combined organic layers were washedwith water (2×200 ml) and brine (200 ml), dried (Na₂SO₄) filtered andconcentrated under reduced pressure. The crude product upon purificationby flash chromatography (silica-gel; EtOAc-PE; 10:90 to 20:80) affordedthe desired product (27.0 g, 80%).

Step 6:3-Bromo-1-methyl-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole

Oxone (49.33 g, 160.7 mmol, 5.0 eq) in water (150 ml) was added to asolution of3-bromo-1-methyl-5-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)-1H-pyrazole(13.5 g, 32.15 mmol, 1.0 eq) in MeOH (350 ml) at RT and stirred for 18h. After completion of the reaction, MeOH was distilled-off underreduced pressure. The residue was made alkaline by addition of sat. aq.NaHCO₃ (200 ml) and extracted with EtOAc (3×150 ml). The organic layerwas washed with water (2×150 ml) and brine (100 ml), dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue uponpurification by flash chromatography (silica-gel; EtOAc-PE; 10:90 to30:70) afforded the desired product (9.0 g, 71%).

Step 7:3-Bromo-1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A solution of3-bromo-1-methyl-5-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole(18.0 g, 39.82 mmol, 1.0 eq) in THF (400 ml) was cooled to −78° C. andt-BuOK (1 M in THF, 80.0 ml, 79.65 mmol, 2.0 eq) was added dropwise. Themixture was stirred for 30 min and Mel (6.45 ml, 99.60 mmol, 2.5 eq) wasadded. The resulting mixture was allowed to warm to RT and stir for 18h. The RM was quenched with sat. aq. NH₄Cl (200 ml) and water (200 ml),and extracted with EtOAc (3×200 ml). The combined organic layers werewashed with water (2×200 ml) and brine (200 ml), dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue uponpurification flash chromatography (silica gel; EtOAc PE; 15:85 to 30:70)afforded [cis rac]3-bromo-1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole(8.5 g, 45%) [TLC system: EtOAc PE; 1:1; Rf: 0.50] and [trans rac]3-bromo-1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)-sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole(1.0 g) [TLC system: EtOAc PE; 1:1; Rf: 0.60].

Step 8:1-Methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-1H-pyrazole

A stirred solution of [cis rac]3-bromo-1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole(100 mg, 0.214 mmol, 1.0 eq), DIPEA (1.15 ml, 0.642 mmol, 3.0 eq) andsodium thiomethoxide (30 mg, 0.642 mmol, 3.0 eq) in toluene (15 ml) wasdegassed for 10 min, and Xantphos (14 mg, 0.0214 mmol, 0.1 eq) followedby Pd₂(dba)₃ (14 mg, 0.15 mmol, 0.07 eq) were added. The mixture wasagain degassed for 5 min. The resulting mixture was heated to 110° C.and stirred for 16 h under Ar. The RM was diluted with water (25 ml) andextracted with EtOAc (2×20 ml). The combined organic extracts werewashed with water (2×20 ml) and brine (25 ml), dried (Na₂SO₄) andconcentrated under reduced pressure. The residue upon purification byflash chromatography (silica gel; EtOAc in PE; 50:50 to 60:40) afforded[cis rac]1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)-phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-1H-pyrazole(60 mg, 64%). In another batch [cis rac]3-bromo-1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)-phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole(1.5 g) was transformed into [cis rac]1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-1H-pyrazole(900 mg; 64%).

Step 9:1-Methyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole

Oxone (3.20 g, 10.37 mmol, 5.0 eq) in water (20 ml) was added to asolution of [cis rac]1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-3-(methylthio)-1H-pyrazole(900 mg, 2.07 mmol, 1.0 eq) in MeOH (60 ml) at RT and the mixture wasstirred for 18 h. The RM was concentrated under reduced pressure, andthe residue made alkaline by addition of sat. aq. NaHCO₃ (70 ml) andextracted with EtOAc (3×50 ml). The organic layer was washed with water(2×75 ml) and brine (75 ml), dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The residue upon purification by flashchromatography (silica-gel; EtOAc-PE; 60:70 to 70:30) afforded [cis rac]1-methyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]-sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole(700 mg, 72%) [TLC system: EtOAc-PE; 1:1, Rf: 0.30].

Chiral resolution of [cis rac]1-methyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole

[Cis-rac]1-methyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazolewas subjected to chiral prep-SFC purification to give 180 mg of[cis-EN1] SC-429 and 190 mg [cis-EN2] SC-430. Preparative SFCConditions: Column/dimensions: Chiralpak AD-H (250×30) mm; CO2: 50%; Cosolvent: 450% MeOH; Total Flow: 100 g/min; Back Pressure: 100 bar; UV:214 nm.

[cis-EN1] SC-429—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 30° C.,4 g/min, 100 bar, 40% MeOH, Ret. Time 1.46 min

[cis-EN2] SC-430—analytical SFC: Chiralcel OJ-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 30% MeOH, Ret. Time 3.65 min

[Trans rac]1-methyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole

The corresponding [trans rac] isomer was prepared in analogy to steps 8& 9 starting from [trans rac]3-bromo-1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazoleto yield [trans-rac]1-methyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazoleSC-433 (48 mg) [TLC system: EtOAc-PE; 2:3; Rf: 0.40].

3-Cyclopropyl-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole(Example 91)

For steps 1 to 7 see Example 90.

Step 8:3-Cyclopropyl-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole

To a stirred solution of [cis rac]3-bromo-1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole(1.5 g, 3.21 mmol, 1.0 eq) and cyclopropyl boronic acid (830 mg, 9.63mmol, 3.0 eq) in toluene (100 ml) was added Cs₂CO₃ (3.14 g, 9.63 mmol,3.0 eq). The mixture was degassed for 15 min, and Pd(dppf)Cl₂CH₂Cl₂ (176mg, 0.193 mmol, 0.06 eq) was added. It was again degassed for 10 min.The resulting mixture was heated to 110° C. and stirred for 16 h underAr. The RM was diluted with EtOAc (60 ml) and filtered. The filtrate waswashed with washed with water (60 ml) and brine (60 ml), dried (Na₂SO₄)and concentrated under reduced pressure. The residue upon purificationby flash chromatography (silica gel; EtOAc in PE; 50:50 to 60:40)afforded [cis rac]3-cyclopropyl-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole(600 mg, 43%) [TLC system: EtOAc-PE; 1:1; Rf: 0.40].

Chiral resolution of [cis rac]3-cyclopropyl-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole

[Cis rac]3-cyclopropyl-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazolewas subjected to chiral prep-SFC purification to give 170 mg of[cis-EN1] SC-431 and 170 mg [cis-EN2] SC-432. Preparative SFCConditions: Column/dimensions: Chiralpak IC (250×30) mm; CO2: 55%; Cosolvent: 45% MeOH; Total Flow: 60 g/min; Back Pressure: 100 bar.

[cis-EN1] SC-431—analytical SFC: Chiralpak IC (250×4.6 mm 5μ), 30° C., 3g/min, 100 bar, 35% of 0.5% DEA in MeOH, Ret. Time 2.09 min

[cis-EN2] SC-432—analytical SFC: Chiralpak IC (250×4.6 mm 5μ), 30° C., 3g/min, 100 bar, 35% of 0.5% DEA in MeOH, Ret. Time 3.03 min

[Trans rac]3-cyclopropyl-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole

The corresponding [trans rac] isomer was prepared in analogy to step 8starting from [trans rac]3-bromo-1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazoleto yield [trans-rac]3-cyclopropyl-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazoleSC-434 (50 mg) [TLC system: EtOAc-PE; 2:3; Rf. 0.40].

General reaction scheme for the preparation of examples 100 to 107(SC-500 to SC-508)

2-Bromo-6-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

Step 1: 2-(6-Bromopyridin-2-yl)tetrahydro-2H-pyran-4-yl methanesulfonate

The first step was carried out in analogy to the synthesis of2-isopropoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine.

Step 2:2-Bromo-6-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred solution of 2-(6-bromopyridin-2-yl)tetrahydro-2H-pyran-4-ylmethanesulfonate (15 g, 44.77 mmol) in DMF (100 mL) was added Cs₂CO₃(14.5 g, 44.77 mmol), 3-(trifluoromethyl)benzenethiol (6.8 mL, 53.73mmol) at RT and stirred for 16 h at 40° C. The RM was diluted with water(30 mL), and extracted into EtOAc (2×50 mL), washed could water (2×20mL), and brine (30 mL), dried over anhydr. Na₂SO₄ and evaporated undervacuum. The crude was purified by silica gel (100-200 mesh) CC using 5%EtOAc in PE as eluent to get the product (12 g, −53% over 2 steps) as aliquid.

Step 3:2-Bromo-6-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred solution of2-Bromo-6-(4-((3-(trifluoromethyl)phenyl)thio)tetrahydro-2H-pyran-2-yl)pyridine(12 g, 28.7 mmol) in EtOH (200 mL) was added oxone (26.5 g, 86.33 mmol)in water (100 mL) and stirred at RT for 16 h. The RM was evaporatedunder vacuum, extracted with EtOAc (2×50 mL), washed with brine (30 mL),dried over anhydr. Na₂SO₄ and evaporated vacuum. The crude was purifiedby silica gel (100-200 mesh) CC using 10% EtOAc in PE as eluent to getcompound 4 (12 g, −93%) as a liquid.

Step 4:2-bromo-6-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

To a stirred solution of2-Bromo-6-(4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(5 g, 11.13 mmol) in THF (50 mL) at −78° C. under dry atmosphere wasadded 1M KOt-Bu (22.26 mL, 22.26 mmol), stirred for 15 min then addedMel (1.7 mL, 27.82 mmol) after addition slowly allowed to RT stirred for16 h. The RM was cool to 0° C. quenched with ice water (20 mL), andextracted into EtOAc (2×50 mL), dried over anhydr. Na₂SO₄ and evaporatedunder vacuum. The crude product was purified by silica gel (100-200mesh) CC using 20% EtOAc in PE as eluent to get the product (5.0 g,˜98%) as white solid.

¹H NMR (400 MHz, DMSO-d₆) of [cis-rac]2-bromo-6-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine:δ 8.22 (d, J=7.6 Hz, 1H), 8.18 (d, J=7.6 Hz, 1H), 8.04 (s, 1H), 7.95 (t,J=8.0 Hz, 1H), 7.77 (t, J=7.8 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.47 (d,J=7.6 Hz, 1H), 4.61 (dd, J=11.2, 2.4 Hz, 1H), 4.10-4.03 (m, 1H),3.78-3.68 (m, 1H), 2.13-2.08 (m, 1H), 1.95-1.91 (m, 1H), 1.86-1.83 (m,1H), 1.50 (s, 3H), 1.47-1.43 (m, 1H).

2-Bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine

The steps 1 to 4 were carried out in analogy to the synthesis of2-Bromo-6-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine¹H NMR (400 MHz, DMSO-d₆) of [cis-rac]2-Bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine:δ 8.35 (d, J=2.4 Hz, 1H), 8.22-8.15 (m, 2H), 8.05 (s, 1H), 7.94 (t,J=7.8 Hz, 1H), 7.71 (dd, J=8.2, 2.6 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H),4.64 (dd, J=11.2, 2.0 Hz, 1H), 4.07 (dd, J=11.8, 4.2 Hz, 1H), 3.74-3.68(m, 1H), 2.14-2.10 (m, 1H), 1.92-1.85 (m, 1H), 1.79-1.75 (m, 1H), 1.49(s, 3H), 1.48-1.47 (m, 1H).

General procedure for the coupling of2-Bromo-6-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(A) and2-Bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(B) with amines

The amine (0.1 mmol), K₃PO₄ (0.02 g, 0.4 mmol), CuI (0.01 g, 0.05 mmol)were mixed in a capped glass vessel.2-Bromo-6-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(A) or2-Bromo-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)pyridine(B) (0.46 g, 0.1 mmol) and N,N′-Dimethylethylendiamine (0.2 mL, 1.8mmol) were added and the mixture was stirred at 120° C. for 16 h. The RMwas quenched with water (3 mL) and extracted into DCM (3×3 mL). Thecrude product was purified by HPLC.

cis/ Cpd No. A/B Amine trans Product SC-500/ B (5-Methyl-3- cis[(5-Methyl-isoxazol-3-yl)-methyl]-[5-[4- Example isoxazolyl)-methyl-4-[[3- 100 methylamine(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine SC-501/ B 2-oxa-7- cis7-[5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]- Example aza-sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]- 101 spiro[3.5]-2-oxa-7-azaspiro[3.5]nonane nonane SC-502/ B 2-(methyl- cis2-[Methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)- Example amino)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]- 102 ethanolpyridin-2-yl]-amino]-ethanol SC-503/ A (5-Methyl-3- cis[(5-Methyl-isoxazol-3-yl)-methyl]-[6-[4- Example isoxazolyl)-methyl-4-[[3- 103 methylamine(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine SC-504/ A 2-oxa-7- cis7-[6-[4-Methyl-4-[[3-(trifluoromethyl)- Example aza-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]- 104 spiro[3.5]-pyridin-2-yl]-2-oxa-7-azaspiro[3.5]nonane nonane SC-505/ A tetrahydro-cis [6-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]- Example 2H-pyran-4-sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]- 105 aminetetrahydro-pyran-4-yl-amine SC-506/ A 2-(methyl- cis2-[Methyl-[6-[4-methyl-4-[[3-(trifluoromethyl)- Example amino)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]- 106 ethanolpyridin-2-yl]-amino]-ethanol SC-508/ A Cyclopropyl cisCyclopropyl-[6-[4-methyl-4-[[3- Example amine(trifluoromethyl)phenyl]sulfonyl]-tetrahydro- 108pyran-2-yl]-pyridin-2-yl]-amine

1-Ethyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole(Example 109)

The synthesis was carried out in analogy to the method described forExample 90 to yield [cis rac]1-ethyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole(800 mg, step 9: 74%) [TLC system: EtOAc-pet-ether; 1:1; Rf. 0.30].

Chiral resolution of [cis rac]1-ethyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole

[Cis rac]1-ethyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazolewas subjected to chiral prep-SFC purification to give 2000 mg of[cis-EN1] SC-509 and 205 mg [cis-EN2] SC-510. Preparative SFCConditions: Column/dimensions: Chiralcel OJ-H (250×30) mm; CO2: 75%; Cosolvent: 25% MeOH; Total Flow: 100 g/min; Back Pressure: 100 bar, UV:216 nm.

[cis-EN1] SC-509—analytical SFC: Chiralcel OJ-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 15% of MeOH, Ret. Time 2.83 min

[cis-EN2] SC-510—analytical SFC: Chiralcel OJ-H (250×4.6 mm 5μ), 30° C.,3 g/min, 100 bar, 15% of MeOH, Ret. Time 3.85 min

[Trans rac]1-ethyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole

[Trans rac]1-ethyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazoleSC-511 (55 mg) [TLC system: EtOAc-pet-ether; 1:1; Rf: 0.35] was preparedaccording to the method described for SC-433.

3-(Difluoro-methoxy)-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole(Example 110)

For steps 1 to 7 see Example 90.

Step 8 & 9:1-Methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-ol

A stirred solution of3-bromo-1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole(2 g, 4.282 mmol, 1.0 eq), Bis-pinacolato diboron (4.35 g, 17.13 mmol,4.0 eq) and KOAc (1.25 g, 12.85 mmol, 3.0 eq) in DMF (100 ml) wasdegassed for 15 min. PdCl₂(dppf)₂ CH₂Cl₂ (244 mg, 0.30 mmol, 0.07 eq)was added and it was again degassed again for 10 min. The resultingmixture was heated to 120° C. and stirred for 36 h under Ar. The RM wasconcentrated under reduced pressure. The residue was diluted with water(100 ml) and extracted with EtOAc (2×100 ml). The combined organicextracts were washed with water (2×100 ml) and brine (100 ml), dried(Na₂SO₄) and concentrated under reduced pressure. To the crude product(4.0 g), dissolved in THF (100 ml), was added NaOH (1.55 g, 38.91 mmol,5.0 eq) in water (20 ml) at 10° C. This was followed by dropwiseaddition of 30% aq. hydrogen peroxide solution (4.5 ml, 38.91 mmol, 5.0eq). The RM was stirred at RT for 16 h. The RM was diluted with water(100 ml) and acidified to pH ˜3-4 with 1N aq. HCl. It was extracted withEtOAc (3×100 ml) and the combined organic layers were washed with water(2×100 ml) and brine (100 ml), dried over anhydr. Na₂SO₄, filtered andconcentrated under reduced pressure. The residue upon purification byflash chromatography (silica gel, MeOH-DCM; 0:100 to 5:95), followed bytrituration and filtration with Et₂O (50 ml) afforded [cis rac]1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-ol(850 mg, 49%; over 2 steps).

Step 10:3-(Difluoro-methoxy)-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole

To a stirred solution of [cis rac]1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-ol(1.7 g, 4.21 mmol, 1.0 eq) in DMF (80 ml) was added K₂CO₃(1.70 g, 12.62mmol, 3.0 eq). The RM was heated to 90° C. and at this temperaturetreated with Freon gas (balloon pressure) over a period of 2 h. The RMwas then stirred at 90° C. for another 4 h. The RM was concentratedunder reduced pressure. The residue was diluted with water (100 ml) andextracted with EtOAc (3×75 ml). The combined organic layers were washedwith water (2×75 ml) and brine (75 ml), dried over anhydr. Na₂SO₄,filtered and concentrated under reduced pressure. The residue uponpurification by flash chromatography (silica gel, EtOAc PE; 40:60 to60:40), afforded [cis rac]3-(difluoro-methoxy)-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole(550 mg, 28%) [TLC system: EtOAc PE; 7:3; Rf: 0.60].

Chiral resolution of [cis rac]3-(difluoro-methoxy)-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole

[Cis rac]3-(difluoro-methoxy)-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazolewas subjected to chiral prep-SFC purification to give 170 mg of[cis-EN1] SC-512 and 175 mg [cis-EN2] SC-513. Preparative SFCConditions: Column/dimensions: Chiralpak AD-H (250×30) mm; CO2: 50%; Cosolvent: 50% MeOH; Total Flow: 90 g/min; Back Pressure: 100 bar, UV: 271nm.

[cis-EN1] SC-512—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 30° C.,5 g/min, 100 bar, 40% of MeOH, Ret. Time 1.31 min

[cis-EN2] SC-513—analytical SFC: Chiralpak AD-H (250×4.6 mm 5μ), 30° C.,5 g/min, 100 bar, 40% of MeOH, Ret. Time 5.52 min

[Trans rac]3-(difluoro-methoxy)-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole

The corresponding [trans rac] isomer was prepared in analogy to steps 8to 10 starting from [trans rac]3-bromo-1-methyl-5-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazoleto yield [trans-rac]3-(difluoro-methoxy)-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazoleSC-514 (20 mg) [TLC system: EtOAc PE; 7:3; Rf: 0.65].

Analytical Data:

Material and Methods for LC/MS Analytics: Hardware: Coupled Agilent 1290Infinity UHPLC-TOF System; LC-Module: MTP-Handler: Agilent, ModelBenchCel 2R; Themostatic Control Autoinjector: Agilent, Modell G4226A;Column oven: Agilent, Model G1316C; DAD: Agilent, Model G4212A; BinaryPump: Agilent, Model G4220A; Time Of Flight Mass Spectrometer: Agilent6224; Ion source: Dual ESI; Column: Supplier: Waters; Type: Acquity UPLCHSS T3 1.8 μm (Part No. 186003538); Dimensions: 2.1×50 mm; Eluents:Eluent A: Water from Millipore Ultrapure water System: Milli-Q Integral3+0.1% Formic acid; Eluent B: Acetonitrile, Merck KGaA: LiChrosolvHypergrade for LC-MS (1.00029.9010)+0.1% Formic acid; Formic acid: MerckKGaA: Suprapure 98-100% (1.11670.1000); LC-Method: Flow: 2.5 mL/min;Runtime: 1.2 min; Gradient: Start 2% B, 1 min 100% B, 1.09 min 100% B,1.11 min 2% B, 1.2 min 2% B Stop; Columntemperature: 80° C.; UV: 190-400nm; MS-Method: Ion Polarity: Positive; Gas Temperature: 325° C.; GasFlow: 10 mL/min

The following tables summarize the LC-MS analytical data

Ex. cis/ Cpd Target Mass UV₂₅₄- No. trans No. Mass Found purity 1 cisSC-100 463.073 Yes 100 1 cis SC- 463.073 Yes 100 101 2 cis SC- 425.127Yes 100 102 2 cis SC- 425.127 Yes 100 103 3 cis SC- 463.073 Yes 100 1043 cis SC- 463.073 Yes 100 105 4 cis SC- 467.099 Yes 100 106 4 trans SC-467.099 Yes 100 107 4 cis SC- 467.099 Yes 100 108 4 trans SC- 467.099Yes 100 109 5 cis SC- 458.073 Yes 100 200 5 cis SC- 458.073 Yes 95 201 6cis SC- 430.117 Yes 100 202 6 cis SC- 430.117 Yes 100 203 7 cis SC-426.122 Yes 100 204 7 cis SC- 426.122 Yes 100 205 8 cis SC- 430.117 Yes100 206 8 cis SC- 430.117 Yes 100 207 9 cis SC- 443.138 Yes 100 300 9cis SC- 443.138 Yes 98 301 9 trans SC- 443.138 Yes 100 302 10 trans SC-413.127 Yes 100 303 11 cis SC- 454.079 Yes 97 304 11 cis SC-305 454.079Yes 99 14 cis SC- 453.083 Yes 100 306 14 trans SC- 453.083 Yes 100 30712 cis SC- 453.083 Yes 100 308 12 cis SC- 453.083 Yes 100 309 12 transSC- 453.083 Yes 100 310 12 trans SC- 453.083 Yes 100 311 13 cis SC-413.127 Yes 100 312 13 cis SC- 413.127 Yes 100 313 13 trans SC- 413.127Yes 99 314 14 cis SC- 453.083 Yes 100 315 14 cis SC- 453.083 Yes 100 31615 cis SC- 427.143 Yes 100 317 15 cis SC- 427.143 Yes 100 318 15 transSC- 427.143 Yes 100 319 16 cis SC- 413.127 Yes 100 323 16 cis SC-413.127 Yes 100 324 17 cis SC- 425.127 Yes 100 325 17 cis SC- 425.127Yes 100 326 18 cis SC- 426.122 Yes 100 327 18 cis SC- 426.122 Yes 100328 18 trans SC- 426.122 Yes 100 329 19 cis SC- 416.102 Yes 100 110 19cis SC- 416.102 Yes 100 111 20 cis SC- 429.122 Yes 100 112 20 cis SC-429.122 Yes 100 113 20 trans SC- 429.122 Yes 100 114 21 cis SC- 453.083Yes 100 115 21 cis SC- 453.083 Yes 100 116 22 cis SC- 455.138 Yes 100117 22 cis SC- 455.138 Yes 100 118 23 cis SC- 481.064 Yes 100 119 23 cisSC- 481.064 Yes 100 120 24 cis SC- 444.058 Yes 100 121 24 cis SC-444.058 Yes 100 122 25 cis SC- 426.067 Yes 100 123 25 cis SC- 426.067Yes 100 124 26 cis SC- 418.117 Yes 100 125 26 cis SC- 418.117 Yes 100126 27 trans SC- 416.102 Yes 100 127 27 cis SC- 416.102 Yes 100 128 27cis SC- 416.102 Yes 100 129 28 cis SC- 497.034 Yes 100 130 28 cis SC-497.034 Yes 100 131 29 cis SC- 456.133 Yes 100 132 29 cis SC- 456.133Yes 100 133 30 cis SC- 483.019 Yes 100 150 30 cis SC- 483.019 Yes 100151 30 trans SC- 483.019 Yes 100 152 30 trans SC- 483.019 Yes 100 153 31cis SC- 463.073 Yes 100 154 31 cis SC- 463.073 Yes 100 155 31 trans SC-463.073 Yes 100 156 31 trans SC- 463.073 Yes 100 157 32 SC- 415.106 Yes100 158 33 cis SC- 483.094 Yes 100 208 33 cis SC- 483.094 Yes 100 209 34cis SC- 477.071 Yes 98 210 34 cis SC- 541.051 Yes 94 211 35 cis SC-513.070 Yes 100 212 35 cis SC- 513.070 Yes 100 213 36 cis SC- 515.025Yes 100 214 36 cis SC- 515.025 Yes 100 215 37 cis SC- 497.034 Yes 100216 37 cis SC- 497.034 Yes 100 217 38 cis SC- 513.029 Yes 100 218 38 cisSC- 513.029 Yes 100 219 39 cis SC- 547.056 Yes 100 220 39 cis SC-547.056 Yes 96 221 40 cis SC- 531.061 Yes 100 222 40 cis SC- 531.061 Yes100 223 41 cis SC- 493.084 Yes 100 224 41 cis SC- 493.084 Yes 100 225 42cis SC- 497.034 Yes 100 226 42 cis SC- 497.034 Yes 100 227 43 cis SC-515.066 Yes 100 228 43 cis SC- 515.066 Yes 100 229 43 cis SC- 515.066Yes 100 230 43 cis SC- 515.066 Yes 100 231 44 cis SC- 481.040 Yes 100232 44 cis SC- 481.040 Yes 100 233 44 cis SC- 481.040 Yes 100 234 44 cisSC- 481.040 Yes 100 235 45 cis SC- 469.054 Yes 100 236 45 cis SC-469.054 Yes 100 237 46 cis SC- 430.117 Yes 100 238 46 cis SC- 430.117Yes 100 239 47 cis SC- 458.073 Yes 100 240 47 cis SC- 458.073 Yes 100241 47 cis SC- 458.073 Yes 100 242 48 cis SC- 419.057 Yes 100 243 48 cisSC- 419.057 Yes 100 244 49 cis SC- 445.117 Yes 100 245 49 cis SC-445.117 Yes 100 246 49 trans SC- 445.117 Yes 100 247 50 cis SC- 429.122Yes 100 248 50 cis SC- 429.122 Yes 100 249 51 cis SC- 431.101 Yes 100250 51 cis SC- 431.101 Yes 100 251 50 trans SC- 429.122 Yes 100 252 52cis SC- 481.098 Yes 100 253 52 cis SC- 481.098 Yes 100 254 53 cis SC-433.097 Yes 100 255 53 cis SC- 433.097 Yes 100 256 54 cis SC- 433.097Yes 100 257 54 cis SC- 433.097 Yes 100 258 54 trans SC- 433.097 Yes 100259 55 cis SC- 440.102 Yes 100 260 55 cis SC- 440.102 Yes 100 261 56 cisSC- 477.089 Yes 100 262 56 cis SC- 477.089 Yes 100 263 57 cis SC-479.044 Yes 100 264 57 cis SC- 479.044 Yes 100 265 58 cis SC- 529.065Yes 100 266 58 cis SC- 529.065 Yes 100 267 59 cis SC- 529.065 Yes 100268 59 cis SC- 529.065 Yes 100 269 60 cis SC- 503.105 Yes 100 270 60 cisSC- 503.105 Yes 100 271 61 cis SC- 428.138 Yes 100 330 61 cis SC-428.138 Yes 100 331 62 cis SC- 440.138 Yes 100 332 62 trans SC- 440.138Yes 100 333 62 cis SC- 440.138 Yes 100 334 63 SC- 399.112 Yes 100 335 64cis SC- 463.073 Yes 100 336 65 cis SC- 463.006 Yes 100 337 64 cis SC-463.073 Yes 100 338 67 SC- 429.122 Yes 100 339 68 cis SC- 487.044 Yes100 340 69 trans SC- 385.096 Yes 100 341 70 SC- 439.068 Yes 100 342 71cis SC- 456.094 Yes 100 343 71 trans SC- 456.094 Yes 100 344 71 cis SC-456.094 Yes 100 345 72 cis SC- 425.127 Yes 100 346 72 trans SC- 425.127Yes 100 347 72 cis SC- 425.127 Yes 100 348 74 SC- 439.068 Yes 100 350 75cis SC- 453.083 Yes 100 351 75 trans SC- 453.083 Yes 100 352 76 cis SC-415.106 Yes 100 353 76 cis SC- 415.106 Yes 100 354 77 cis SC- 531.061Yes 100 355 77 cis SC- 531.061 Yes 100 356 78 cis SC- 454.154 Yes 100400 78 cis SC- 454.154 Yes 100 401 79 cis SC- 452.113 Yes 100 402 79 cisSC- 452.113 Yes 100 403 80 cis SC- 459.133 Yes 100 404 80 cis SC-459.133 Yes 100 405 78 trans SC- 454.154 Yes 100 406 79 trans SC-452.113 Yes 100 407 81 cis SC- 414.122 Yes 100 408 81 cis SC- 414.122Yes 100 409 82 cis SC- 416.102 Yes 100 410 82 cis SC- 416.102 Yes 100411 81 trans SC- 414.122 Yes 100 412 83 cis SC- 429.133 Yes 100 413 83cis SC- 429.133 Yes 100 414 84 cis SC- 416.102 Yes 100 415 84 cis SC-416.102 Yes 100 416 85 trans SC- 451.088 Yes 100 417 85 cis SC- 451.088Yes 100 418 85 cis SC- 451.088 Yes 100 419 80 trans SC- 459.133 Yes 59420 86 cis SC- 429.133 Yes 100 421 86 cis SC- 429.133 Yes 98 422 87 cisSC- 416.102 Yes 100 423 87 cis SC- 416.102 Yes 100 424 88 cis SC-459.088 Yes 100 425 88 cis SC- 459.088 Yes 100 426 89 cis SC- 485.049Yes 100 427 89 cis SC- 485.049 Yes 100 428 90 cis SC- 466.084 Yes 100429 90 cis SC- 466.084 Yes 100 430 91 cis SC- 428.138 Yes 100 431 91 cisSC- 428.138 Yes 100 432 90 trans SC- 466.084 Yes 100 433 91 trans SC-428.138 Yes 100 434 88 trans SC- 459.088 Yes 100 435 92 cis SC- 495.039Yes 100 436 92 cis SC- 495.039 Yes 100 437 89 trans SC- 485.049 Yes 86438 93 cis SC- 463.008 Yes 90 439 93 cis SC- 463.008 Yes 100 440 94trans SC- 477.089 Yes 100 441 95 cis SC- 477.089 Yes 100 442 95 cis SC-477.089 Yes 100 443 96 cis SC- 495.080 Yes 100 444 96 cis SC- 495.080Yes 100 445 97 cis SC- 471.094 Yes 100 446 97 cis SC- 471.094 Yes 100447 95 trans SC- 477.089 Yes 100 448 98 cis SC- 493.084 Yes 100 449 98cis SC- 493.084 Yes 100 450 98 trans SC- 493.084 Yes 100 451 99 cis SC-454.042 Yes 100 452 99 cis SC- 454.042 Yes 100 453 96 trans SC- 495.080Yes 100 454 100 cis SC- 495.144 Yes 100 500 101 cis SC- 510.180 Yes 100501 102 cis SC- 458.149 Yes 100 502 103 cis SC- 495.144 Yes 100 503 104cis SC- 510.180 Yes 100 504 105 cis SC- 484.164 Yes 100 505 106 cis SC-458.149 Yes 100 506 107 cis SC- 458.149 Yes 98 507 108 cis SC- 440.138Yes 99 508 109 cis SC- 480.100 Yes 100 509 109 cis SC- 480.100 Yes 100510 109 trans SC- 480.100 Yes 72.97 511 110 cis SC- 454.099 Yes 95.34512 110 cis SC- 454.099 Yes 100 513 110 trans SC- 454.099 Yes 100 514100 cis SC- 495.144 Yes 100 5002. Assay Descriptions and Biological Data:2.1 Fluorescence Assay for CaV2.2 Channels Using PotassiumDepolarization to Induce Channel Opening

Human CaV2.2 channels were stably expressed in HEK293 cells togetherwith alpha2-delta and beta subunits of voltage gated calcium channels.In addition, an inwardly rectifying potassium channel (Kir2.3) wasstably expressed in these cells to augment control of the cell membranepotential by the concentration of extracellular potassium ions. Raise ofthe extracellular potassium concentration leads to depolarization of themembrane potential and thus regulates the voltage dependent state ofCaV2.2 channels. For preparation, cells were seeded in blackpoly-D-lysine coated 96-well plates (Becton Dickinson, Biocoat 4640) in100 μL medium [500 mL DMEM/F-12 plus Glutamax (Invitrogen 31331-093)plus 5.5 mL MEM NEAA 100× (Invitrogen 11140-035) plus 50 mL FBSdecomplemented (Invitrogen 10270-106) plus 200 μg/mL Geneticin(Invitrogen 10131-027) plus 50 μg/mL Hygromycin B (Invitrogen 10687-010)plus 2 μg/mL Blasticidin (anti-bl5b Invivo-Gen) plus 0.2 μg/mL Puromycin(A 11138-03)] at a cell density of 30.000 cells per well. Plates wereincubated at 37° C. (5% CO₂) for 20 to 23 h. On the day of experimentmedium was discarded and cells were loaded with Fluo 4 by addition of100 μL of basic assay buffer (10 mM HEPES, 1 mM KCl, 149 mM NaCl, 0.8 mMCaCl₂, 1.7 mM MgCl₂, 10 mM Glucose, 0.1% BSA. pH 7.4) containing 2 μMFluo 4 (Molecular Probes; F-14201), 0.01% pluronic acid (MolecularProbes; P-6866) and 2.5 mM probenecid (Molecular Probes; P36400). Cellswere incubated in the dark at 25° C. for 60 min. Then dye containingbuffer was discarded and 100 μL basic (1 mM KCl) or alternative (30 mMKCl) assay buffer was added. The alternative assay buffer containedaltered concentrations of KCl (30 mM) and NaCl (120 mM) and was used inorder to promote the inactivated channel state. After that 25 μL ofbasic or alternative assay buffer with or without test compound wereadded and cells were incubated again in the dark at 25° C. for 15 min.Fluorescence intensity was measured on a FLIPR 3 instrument (MolecularDevices Corp., Sunnyvale, Calif.) with excitation at 480 nm and emissionat 535 nm. After continuously reading fluorescence for 30 sec, 50 μL ofbasic assay buffer containing 210 mM KCl (NaCl omitted) were added fordepolarization. Peak fluorescent signal intensity was determined and theamplitude of the peak signal, normalized to base line, was used tomeasure channel inhibition by test compounds.

The following tables summarize the inhibitory activity of exemplifiedcompounds according to the present invention.

Cpd Activity No. Category SC- C 100 SC- B 101 SC- A 102 SC- A 103 SC- B104 SC- B 105 SC- A 106 SC- A 107 SC- A 108 SC- B 109 SC- B 200 SC- B201 SC- B 202 SC- B 203 SC- B 204 SC- A 205 SC- C 206 SC- C 207 SC- A300 SC- A 301 SC- A 302 SC- B 303 SC- B 304 SC- A 305 SC- A 306 SC- A307 SC- A 308 SC- A 309 SC- A 310 SC- A 311 SC- C 312 SC- C 313 SC- C314 SC- A 315 SC- A 316 SC- C 317 SC- B 318 SC- C 319 SC- B 323 SC- B324 SC- A 325 SC- A 326 SC- B 327 SC- A 328 SC- A 329 SC- B 110 SC- B111 SC- C 112 SC- B 113 SC- B 114 SC- B 115 SC- A 116 SC- B 117 SC- A118 SC- B 119 SC- B 120 SC- C 121 SC- B 122 SC- B 123 SC- C 124 SC- C125 SC- B 126 SC- C 127 SC- B 128 SC- C 129 SC- B 130 SC- B 131 SC- B132 SC- A 133 SC- A 158 SC- B 208 SC- A 209 SC- A 210 SC- B 212 SC- B213 SC- C 214 SC- B 215 SC- C 216 SC- C 217 SC- B 218 SC- A 219 SC- A220 SC- B 221 SC- B 222 SC- B 223 SC- B 224 SC- B 225 SC- B 226 SC- B227 SC- A 228 SC- B 229 SC- B 230 SC- B 231 SC- C 233 SC- C 234 SC- C235 SC- B 236 SC- B 237 SC- B 238 SC- B 239 SC- C 240 SC- B 241 SC- C242 SC- A 243 SC- B 244 SC- B 245 SC- A 246 SC- B 247 SC- B 248 SC- B249 SC- C 251 SC- B 252 SC- B 253 SC- A 254 SC- A 255 SC- B 256 SC- B257 SC- A 258 SC- A 259 SC- A 260 SC- C 261 SC- B 262 SC- B 263 SC- C265 SC- A 266 SC- A 267 SC- B 268 SC- A 269 SC- B 270 SC- B 271 SC- B330 SC- A 331 SC- B 332 SC- A 333 SC- B 334 SC- C 335 SC- C 336 SC- A337 SC- B 338 SC- A 339 SC- A 340 SC- C 341 SC- B 342 SC- B 343 SC- B344 SC- A 345 SC- B 346 SC- A 347 SC- A 348 SC- A 349 SC- A 350 SC- A351 SC- A 352 SC- B 353 SC- A 354 SC- B 355 SC- A 356 SC- A 400 SC- A401 SC- B 402 SC- B 403 SC- B 404 SC- B 405 SC- A 406 SC- B 407 SC- B408 SC- B 409 SC- C 410 SC- C 411 SC- B 412 SC- B 413 SC- B 414 SC- B415 SC- B 416 SC- A 417 SC- A 418 SC- A 419 SC- B 420 SC- B 421 SC- B422 SC- C 423 SC- B 424 SC- A 425 SC- A 426 SC- A 427 SC- A 428 SC- C429 SC- B 430 SC- B 431 SC- A 432 SC- C 433 SC- B 434 SC- A 435 SC- C436 SC- B 437 SC- A 438 SC- C 439 SC- B 440 SC- B 441 SC- C 442 SC- B444 SC- C 445 SC- B 446 SC- A 447 SC- B 449 SC- C 450 SC- C 451 *%-Inhib (CaV2.2) @3 μM @30 mM KCl: “A”: %-Inhibition >95%; “B”:%-Inhibition >75% up to ≦95%; “C”: %-Inhibition >40% up to ≦75%, “D”:%-Inhibition >30% up to ≦40%.2.2 Electrophysiological Assessment of Calcium Channel Activity

Patch-clamp recordings were performed using HEK293 cells stablyexpressing human Cav2.2. Cells were plated in T150 flasks and grown ahumidified incubator at 37° C. and under 5% CO₂ to approximately 50-60%confluency. Cells were maintained at 30° C. for 48 hrs prior torecording. On the day of the experiment, cells were harvested withTrypLE cell detachment solution (Invitrogen) diluted to 25% withphosphate buffered saline and maintained in 50% cell culture media, 50%NaCl based external saline (in mM, 140 NaCl, 4 KCl, 1 MgCl₂, 2 CaCl₂, 5Glucose, 10 HEPES, pH 7.4) up to several hours prior to experiment.

Currents were recorded at RT (21-23° C.) using the Patchliner planararray technology (Nanion). Patchliner is a multi-well whole-cellautomated patch clamp device that operates asynchronously with fullyintegrated fluidics. Capacitance and series resistance compensation wasautomated and no correction for liquid junction potential was employed.Leak was subtracted on-line. Whole-cell patch-clamp recordings wereobtained using extracellular saline consisting of (mM): 145 TEA-CI, 10BaCl₂, 10 HEPES, 10 Glucose. The pH was adjusted to 7.35 with NaOH andthe osmolarity was adjusted to 310 mOsm with sucrose. Intracellularsolution consisted of (mM): 50 CsCl, 60 CsF, 10 NaCl, 20 EGTA, 5 BAPTA,10 HEPES. Prior to an experiment, 5 mM MgATP and 0.3 NaGTP were added,the pH was adjusted to 7.2 with CsOH and the osmolarity was adjusted to290 mOsm with sucrose.

A voltage pulse protocol was utilised to assess compound inhibition.Cells were held at a holding potential of −60 mV and channels wereactivated using a 10 ms test pulse to +30 mV activated every 10 seconds(0.1 Hz). Increasing concentrations of compound were applied toindividual cells with 5 minutes at each test concentration. Compoundswere prepared in DMSO as 10 mM stock solutions and subsequent 1:3 serialdilutions performed. Final dilution of 1:1000 in external solutionresulted in a final DMSO concentration of 0.1%. For each cell, currentresponses were normalized to dimethyl sulfoxide vehicle control togenerate concentration-response curves. When multiple doses wereachieved per cell, IC₅₀ values were calculated from the fits of the Hillequation to the data. The form of the Hill equation used was: Relativecurrent=(100/(1+(IC₅₀/conc)^Slope)). A selection of the foregoingexemplified compounds was tested under these conditions: Severalcompounds are potent inhibitors (IC₅₀<5 μM) or even very potentinhibitors (IC₅₀<2 μM).

The invention claimed is:
 1. A compound of formula (I),

wherein m represents 1 or 2; n denotes 0 or 1; Y is selected from thegroup consisting of bond and —C(R³)₂—; wherein each R³ is independentlyselected from the group consisting of H and C₁₋₆-alkyl, or two R³ formtogether with the C-atom connecting them a C₃₋₁₀-cycloalkyl or a 3 to 7membered heterocyclyl; L is —[C(R⁴)₂]_(x)—(X)_(y)—[C(R⁴)₂]_(z), whereinx is 0, 1 or 2, y is 0 or 1 and z is 0 or 1, with the proviso that x≧y;each R⁴ is independently selected from the group consisting of H andC₁₋₆-alkyl, or two R⁴ form together with the C-atom connecting them aC₃₋₁₀-cycloalkyl or a 3 to 7 membered heterocyclyl or two R⁴ formtogether with two adjacent C-atoms connecting them a C₃₋₁₀-cycloalkyl ora 3 to 7 membered heterocyclyl, X is selected from the group consistingof O, S, S(O)₂, N(H) or N(C₁₋₆-alkyl); R¹ is selected from the groupconsisting of H; F; Cl; CN; C₁₋₆-alkyl; C₁₋₆-alkyl-O(R⁵) andC₁₋₆-alkyl-N(R⁵)₂; wherein each R⁵ is independently selected from H orC₁₋₆-alkyl or two R⁵ form together with the N-atom connecting them a 3to 7 membered heterocyclyl; R² is selected from the group consisting ofH; F; Cl; CN; C₁₋₆-alkyl; C₁₋₆-alkyl-O(R⁶) and C₁₋₆-alkyl-N(R⁶)₂;wherein each R⁶ is independently selected from H or C₁₋₆-alkyl or two R⁶form together with the N-atom connecting them a 3 to 7 memberedheterocyclyl; Ar¹ represents aryl or heteroaryl, wherein said aryl orsaid heteroaryl is substituted by zero or one or two or threesubstituents R⁷, Ar² represents heteroaryl, substituted by zero or oneor two or three substituents R⁸, wherein each R⁷ and each R⁸ isindependently selected from the group consisting of F; Cl; Br; I; NO₂;CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; C(═O)—H;C(═O)—C₁₋₆-alkyl; C(═O)—OH; C(═O)—O—C₁₋₆-alkyl; C(═O)—N(H)(OH);C(═O)—NH₂; C(═O)—N(H)(C₁₋₆-alkyl); C(═O)—N(C₁₋₆-alkyl)₂; C(═N—OH)—H;C(═N—OH)—C₁₋₆-alkyl; C(═N—O—C₁₋₆-alkyl)-H;C(═N—O—C₁₋₆-alkyl)-C₁₋₆-alkyl; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; O—C(═O)—O—C₁₋₆-alkyl;O—(C═O)—N(H)(C₁₋₆-alkyl); O—C(═O)—N(C₁₋₆-alkyl)₂; O—S(═O)₂—C₁₋₆-alkyl;O—S(═O)₂—OH; O—S(═O)₂—O—C₁₋₆-alkyl; O—S(═O)₂—NH₂;O—S(═O)₂—N(H)(C₁₋₆-alkyl); O—S(═O)₂—N(C₁₋₆-alkyl)₂; NH₂;N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl;N(H)—C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—NH₂; N(H)—C(═O)—N(H)(C₁₋₆-alkyl);N(H)—C(═O)—N(C₁₋₆-alkyl)₂; N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—NH₂;N(C₁₋₆-alkyl)-C(═O)—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; N(H)—S(═O)₂OH;N(H)—S(═O)₂—C₁₋₆-alkyl; N(H)—S(═O)₂—O—C₁₋₆-alkyl; N(H)—S(═O)₂—NH₂;N(H)—S(═O)₂—N(H)(C₁₋₆-alkyl); N(H)—S(═O)₂N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-S(═O)₂—OH; N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-S(═O)₂—NH₂;N(C₁₋₆-alkyl)-S(═O)₂—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₁₆-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl);S(═O)₂—N(C₁₋₆-alkyl)₂; C₃₋₁₀-cycloalkyl; 3 to 7 membered heterocyclyl;aryl; heteroaryl; O—C₃₋₁₀-cycloalkyl; O-(3 to 7 membered heterocyclyl);O-aryl; O-heteroaryl; N(H)—C₃₋₁₀-cycloalkyl; N(H)-(3 to 7 memberedheterocyclyl); N(H)-aryl; N(H)-heteroaryl;N(C₁₋₆-alkyl)-C₃₋₁₀-cycloalkyl; N(C₁₋₆-alkyl)-(3 to 7 memberedheterocyclyl); N(C₁₋₆-alkyl)-aryl; N(C₁₋₆-alkyl)-heteroaryl;C(═O)—C₃₋₁₀-cycloalkyl; C(═O)-(3 to 7 membered heterocyclyl);C(═O)-aryl; C(═O)-heteroaryl; S(═O)₂—C₃₋₁₀-cycloalkyl; S(═O)₂-(3 to 7membered heterocyclyl); S(═O)₂-aryl; S(═O)₂-heteroaryl;S(═O)(═NR¹³)—C₃₋₁₀-cycloalkyl; S(═O)(═NR¹³)-(3 to 7 memberedheterocyclyl); S(═O)(═NR¹³)-aryl and S(═O)(═NR¹³)-heteroaryl, whereinR¹³ represents H or C₁₋₆-alkyl; wherein in each case said C₁₋₆-alkyl maybe branched or unbranched; unsubstituted or mono- or polysubstituted;and wherein in each case said C₃₋₁₀-cycloalkyl, 3 to 7 memberedheterocyclyl aryl and heteroaryl may be unsubstituted or mono- orpolysubstituted; optionally in the form of a single stereoisomer or amixture of stereoisomers, in form of the free compound and/or aphysiologically acceptable salt and/or a physiologically acceptablesolvate thereof.
 2. A compound according to claim, wherein the compoundof formula (I) is a compound according to formula (II),

or formula (IIa) or (IIb),

wherein each Ar¹, Ar², R¹, R², Y and L are defined according to claim 1.3. A compound according to claim 1, wherein the compound of formula (I)is one diastereomer.
 4. A compound according to claim 3, wherein thecompound of formula (I) is one enantiomer.
 5. A compound according toclaim 1, wherein R² represents H, CH₃, C₂H₅, CH₂CH₂CH₃, CH(CH₃)₂, CH₂OH,CH₂OCH₃, CH₂NH₂, CH₂N(H)CH₃ or CH₂N(CH₃)₂.
 6. A compound according toclaim 1, wherein R¹ represents H, CH₃, C₂H₅, CH₂CH₂CH₃, CH(CH₃)₂, CH₂OH,CH₂OCH₃, CH₂NH₂, CH₂N(H)CH₃ or CH₂N(CH₃)₂.
 7. A compound according toclaim 1, wherein Ar¹ represents phenyl or pyridinyl, substituted by zeroor one or two or three substituents R⁷, wherein each R⁷ is independentlyselected from the group consisting of F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H;CFH₂; C(═O)—C₁₋₆-alkyl; C(═O)—OH; C(═O)—O—C₁₋₆-alkyl; C(═O)—N(H)(OH);C(═O)—NH₂; C(═O)—N(H)(C₁₋₆-alkyl); C(═O)—N(C₁₋₆-alkyl)₂; OH; OCF₃;OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; O—C₁₋₆-alkyl; NH₂; N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;N(H)—S(═O)₂—C₁₋₆-alkyl; SCF₃; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl;S(═O)₂—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl);S(═O)₂—N(C₁₋₆-alkyl)₂; C₃₋₁₀-cycloalkyl; 3 to 7 membered heterocyclyl;O—C₃₋₁₀-cycloalkyl and O-(3 to 7 membered heterocyclyl).
 8. A compoundaccording to claim 1, wherein Ar¹ is represented by subformula SF-I

wherein X is CH or N, R¹⁰ is selected from the group consisting of CF₃;CF₂H; CFH₂; OCF₃; OCF₂H and OCFH₂; and R¹¹ is selected from the groupconsisting of H; F; Cl; CN; CH₃; CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂;CH(CH₃)CH₂CH₃; CH₂CH₂CH₂CH₃; CH₂CH(CH₃)₂; C(CH₃)₃; CF₃; CF₂H; CFH₂;OCF₃; OCH₃; OCH₂CH₃; OCH(CH₃)₂; S(═O)—CH₃ and S(═O)₂—CH₃.
 9. A compoundaccording to claim 1, wherein L is bond, CH₂; C(CH₃)₂; CH(CH₃); CH₂CH₂;CH₂C(CH₃)₂; C(CH₃)₂CH₂; CH₂O; C(CH₃)₂₀; CH(CH₃)O;


10. A compound according to claim 1, wherein Ar² represents pyridinyl,pyrazinyl, pyridazinyl, pyrimidinyl, oxazolyl, isoxazolyl andoxadiazolyl, each substituted by zero, one or two substituents R⁸,wherein each R⁸ is independently selected from the group consisting ofF; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OCF₃; OCF₂H; OCFH₂;O—C₁₋₆-alkyl; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; C₃₋₁₀-cycloalkyl; 3 to 7 membered heterocyclyl; aryl; heteroaryl;O—C₃₋₁₀-cycloalkyl; O-(3 to 7 membered heterocyclyl); O-aryl;O-heteroaryl; C(═O)—C₃₋₁₀-cycloalkyl; C(═O)-(3 to 7 memberedheterocyclyl); C(═O)-aryl; C(═O)-heteroaryl; S(═O)₂—C₃₋₁₀-cycloalkyl;S(═O)₂-(3 to 7 membered heterocyclyl); S(═O)₂-aryl; S(═O)₂-heteroaryl;S(═O)(═NR¹³)—C₃₋₁₀-cycloalkyl; S(═O)(═NR¹³)-(3 to 7 memberedheterocyclyl); S(═O)(═NR¹³)-aryl and S(═O)(═NR¹³)-heteroaryl, whereinR¹³ represents H or C₁₋₆-alkyl.
 11. A compound according to claim 1,wherein Ar² is selected from the group consisting of pyridinyl,pyrazinyl, pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl and oxadiazolyl,each substituted by zero, one or two substituents R⁸, wherein each R⁸ isselected from the group consisting of F; Cl; CN; CH₃; CH₂CH₃; CH₂CH₂CH₃;CH(CH₃)₂; CF₃; CF₂H; CFH₂; OCF₃; OCF₂H; OCFH₂; OCH₃; OCH₂CH₃; OCH(CH₃)₂;S(═O)CH₃; S(═O)CH₂CH₃; S(═O)₂CH₃; S(═O)₂CH₂CH₃; cyclopropyl andO-cyclopropyl.
 12. A compound according to claim 1, which is selectedfrom the group consisting of: 13-Methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine25-Cyclopropyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine35-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine42-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine55-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-[1,2,4]oxadiazole63-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole72-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine82-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole92-Isopropoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine102-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-methyl-pyridine115-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyrimidine122-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine133-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-methyl-pyridine145-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(trifluoromethyl)-pyridine153-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2,6-dimethyl-pyridine162-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-methyl-pyridine173-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine182-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine195-Cyclopropyl-3-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole202-Methyl-5-[[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-pyridine213-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine222-Cyclopropyl-5-[[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-pyridine233-Fluoro-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine242-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-[1,3,4]oxadiazole252-(Difluoro-methyl)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole262-Isopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole272-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,3,4]oxadiazole283-Chloro-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine292-Cyclopropyl-5-[[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-pyrazine303-Chloro-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)pyridine313-Methyl-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)pyridine324-Cyclopropyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-oxazole335-[[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-methoxy]-2-(trifluoromethyl)-pyridine342-[4-Methyl-4-[(3-methylsulfonyl-phenyl)sulfonyl]-tetrahydro-pyran-2-yl]-3-methylsulfonyl-5-(trifluoromethyl)-pyridine352-[4-[[3-(Difluoro-methyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methylsulfonyl-5-(trifluoromethyl)-pyridine363-Chloro-2-[4-[[3-fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine373-Chloro-2-[4-[[3-(difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine383-Chloro-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine393-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine405-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-pyridine413-Methoxy-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine425-Chloro-3-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine433-(Methylsulfinyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine443-Chloro-5-(methylsulfinyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine453-Chloro-5-(difluoro-methyl)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine465-Cyclopropyl-3-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-[1,2,4]oxadiazole472-[4-Ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-[1,3,4]oxadiazole485-Chloro-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine49 2,4-Dimethoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine502-Methoxy-4-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine512-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-4-ol524-(Difluoro-methoxy)-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine533-Fluoro-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine544-Fluoro-2-methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine552-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-isonicotinonitrile563-Methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine573-Chloro-2-[4-[[3-(difluoro-methyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine585-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-y)-3-(methylsulfonyl)pyridine593-(difluoromethoxy)-2-(4-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)tetrahydro-2H-pyran-2-y)-5-(methylsulfonyl)pyridine603-cyclopropyl-2-(4-methyl-4-(3-(trifluoromethyl)phenylsulfonyl)tetrahydro-2H-pyran-2-yl)-5-(methylsulfonyl)pyridine61Dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine622-Cyclopropyl-5-[4-ethyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine632,6-Dimethyl-3-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine642-Methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine652-Bromo-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine672-Isopropoxy-5-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine683-Chloro-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine692-Methyl-6-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine702-(Trifluoromethyl)-5-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine711-Methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-3-(trifluoromethyl)-1H-pyrazole722-Cyclopropyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine742-(Trifluoromethyl)-6-[4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine752-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-6-(trifluoromethyl)-pyridine762-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine773-Methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-5-(trifluoromethyl)-pyridine785-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-pyrrolidin-1-yl-pyridine795-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-2-(1H-[1,2,4]triazol-1-yl)-pyridine802-(2-Methoxy-ethoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine81Methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine822-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine83Dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidin-2-yl]-amine842-Methoxy-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazine852-(Difluoro-methoxy)-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine86Dimethyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrazin-2-yl]-amine875-Methoxy-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyrimidine883-Chloro-5-cyclopropyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine893-Chloro-5-(difluoro-methoxy)-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine901-Methyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole913-Cyclopropyl-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole923-Chloro-2-[4-[[3-(difluoro-methoxy)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine933-Chloro-2-[4-[(3-chlorophenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine943-Methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine952-[4-[[3-(Difluoro-methyl)-5-fluoro-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridine962-[4-[[3-Fluoro-5-(trifluoromethyl)-phenyl]sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-3-methyl-5-methylsulfonyl-pyridine973-Chloro-2-[4-[(3-isopropyl-phenyl)sulfonyl]-4-methyl-tetrahydro-pyran-2-yl]-5-methylsulfonyl-pyridine983-Methyl-5-methylsulfonyl-2-[4-methyl-4-[[3-(trifluoromethyloxy)-phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridine993-[[2-(3-Chloro-5-methylsulfonyl-pyridin-2-yl)-4-methyl-tetrahydro-pyran-4-yl]sulfonyl]-benzonitrile100[(5-Methyl-isoxazol-3-yl)-methyl]-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine1017-[5-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-2-oxa-7-azaspiro[3.5]nonane1022-[Methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amino]-ethanol103[(5-Methyl-isoxazol-3-yl)-methyl]-[6-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine1047-[6-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-2-oxa-7-azaspiro[3.5]nonane105[6-[4-Methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-tetrahydro-pyran-4-yl-amine1062-[Methyl-[6-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amino]-ethanol1072-[Methyl-[5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amino]-ethanol108Cyclopropyl-[6-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-pyridin-2-yl]-amine1091-Ethyl-3-methylsulfonyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazole1103-(Difluoro-methoxy)-1-methyl-5-[4-methyl-4-[[3-(trifluoromethyl)phenyl]sulfonyl]-tetrahydro-pyran-2-yl]-1H-pyrazoleoptionally in the form of a single stereoisomer or a mixture ofstereoisomers, in the form of the free compound and/or a physiologicallyacceptable salt or solvate thereof.
 13. A pharmaceutical compositioncomprising at least one compound according to claim 1.